from Leadership Medica n. 277/2009
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 efficiency, the quest towards increased tolerance and treatment adequacy. Today a new chalange is appearing on the scene and it concerns miniaturization, transportability, wearability and why not the possibility to develop 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 ultrafiltration systems (WUF) and wearable artificial kidneys (WAK). Some of them use extracorporeal blood cleansing as a method of blood purification 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 artificial kidney a reality rather than a dream. A special mention deserves the wearable/portable ultrafiltration system for the therapy of overhydration and congestive heart failure. This system will allow dehospitalization and treatment of patients with less comorbidity and improved tolerance.
Although the first human patients with acute renal failure were treated with a haemodialysis technique in the 1920s , it was only at the end of the second world war that haemodialysis effectively became life saving for acute renal failure. This was due to the purification and commercial availability of unfractionated heparin, an effective extracorporeal anticoagulant, and the pioneering work developing the cellophane drum dialyzer [2,3]. However, haemodialysis remained a treatment for acute renal failure, until the 1960s, following improvements in vascular access  and dialyzer technology , which allowed the long term treatment of patients with end stage kidney failure .
Similarly forms of peritoneal dialysis were used in the 1920s and prior to the second world war . Even following the introduction of a simplified method of irrigating the peritoneal cavity, using a single disposable catheter and commercially available dialysis solutions , peritoneal dialysis essentially remained a treatment for acute renal failure. It was only when Tenckhoff described the use of a permanent indwelling silicone-rubber catheter with Dacron cuffs, that intermittent periodic peritoneal dialysis treatments were possible , and continuous peritoneal dialysis for chronic renal failure was only described in 1976 .
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 fluid intake. Although there are many reports of "wearable" haemodialysis devices, these generally refer to haemofiltration circuits, often using indwelling femoral arterial and venous catheters, and/or arterio-venous shunts . 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 . More sophisticated devices recycled ultrafiltrate by passage through sorbent cartridges . However these pioneers were unable to develop their devices, due to their size and weight, and low clearance rates. It is only recently with the development of miniature pumps, that it has been possible to develop the ideas of these early pioneers, into potentially effective wearable haemodialysis and/or haemofiltration devices.
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 world wide. 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 effluent, so reducing storage requirements would potentially allow more patients to be treated by peritoneal dialysis.
Rationale for a wearable artificial kidney
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 [13-18]. In healthy individuals blood is filtered by the native kidneys 168 hours a week. Obviously, filtering the blood only for 12 hours per week with dialysis (as typically prescribed in the US) is both un-physiologic and most inadequate, resulting in poor quality of life and unacceptable high mortality. As patients are shifted from the typical three-dialysis treatments per week regime to one of daily dialysis, significant improvement of the quality of life was reported (i.e., liberalization of the diet, fluid restrictions, etc.) alongside substantial reductions in medication consumption, complications, psychological symptoms, admissions and hospitalization.  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 cardiovascular disease and stroke, 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 financial healthcare resources. In the US alone, the number of ESRD patients has been growing steadily and 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. 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 in 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 technicians to provide more treatments in the dialysis units, and the reluctance of governmental payers to shoulder the expense of additional procedures [21-27]. Thus, there is a growing need for a practical around-the-clock solution that will afford to ESRD patients the ability of receiving significantly increased dialysis dosages, while increasing efficiency and reducing the overall cost, the need for dedicated brick and mortar and the utilization of manpower. Continuous renal replacement therapy (CRRT) allows significantly higher doses of dialysis but is unsuitable for treating ESRD patients because these 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 Wearable Artificial Kidney (WAK). [16-11]. Listed below are some of the technological challenges to overcome in this endeavor:
- The device must be wearable and therefore, independent of the electrical outlet. However, a device consuming large amounts of energy would require large and heavy energy sources. Thus, the need for light, energy-efficient and cost-effective parts as well as small, light and potent batteries.
- The amount of dialysate has to be minimal. Thus, 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 reconfigured and adapted as the purifying medium, facilitating the use of sterile and pure dialysate in quantity lower than 500cc.
- The patient should be able to wear the device, and ambulate without impinging in his ability to perform activities of daily life. Thus, the need for lightweight and ergonomic design that would be unobtrusive and adapt to the body contour.
- Still remains the issue of the vascular access and the need to remove daily the excess of fluids.
These challenges have been met in developing the prototype of a WAK to be tested in clinical settings. Unique innovations in the development of a miniaturized, dual-channel, adjustable flow, battery operated, pulsatile pump for driving both blood and dialysate through the wearable device, and the miniaturized configuration of micro-dispensing 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 cost of treating ESRD patients. The efficiency of the device was evaluated by achieving the removal of urea, creatinine, potassium, phosphorus and ultrafiltrate in amounts that would normalize the volume status and the above chemistries in uremic humans, if the device would be worn continuously.
The capability of the device to remove fluid steadily from the vascular space an amount of 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 fluid they may ingest. Furthermore, the elimination of excess fluid may well results in a better control of hypertension. In addition, the sodium content of the ultrafiltrate is equal to that of the plasma. Thus, the removal of 1.5 to 2 liters of fluid a day will result in the removal of 13.5 to 18 grams of salt [29-34]. This alone would not only contribute to better control of hypertension, 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 oral intake of both these elements, and the elimination of oral phosphate binders. The high dialysis dose as expressed both in clearances and weekly Urea KT/V, may achieve all the benefits currently demonstrated in daily dialysis schedules. The long-term effects of this technology on the wellbeing of these patients, although expected to be significant, will be the subject of much needed clinical research.
History and development of the conceptual model for a wearable kidney
Although treatment for acute kidney injury was available in the 1960s, treatment for chronic kidney disease 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 haemodialysis for patients with chronic kidney disease was a major technological breakthrough, there were obvious limitations in terms of dietary restriction, fluid 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 centre, typically treated for 8 hour dialysis sessions, unable to go away on holiday. To improve patient lifestyle, home hemodialysis was developed, and became popular in the 1970s. However, even from the start of developing haemodialysis as a treatment from chronic kidney disease, the eventual goal of the early pioneers was to develop a truly wearable device, that would allow the patient to be able to have a more normal lifestyle, yet be treated
The earliest attempts date back to Kolff's team in the 1960s . 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, whilst being treated (35-40).
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 which worked only with venous blood access required a blood pump, and an electrical power source. None of the papers quoted by Professors Shaldon and Lysaght details a battery powered pump to propel blood through the hemofilter, nor describes approved safety features to monitor blood leaks and/or air bubbles.
Fig. 2: Prof. Ronco with a patient wearing the artificial kidney
Recent result with new models of wearable artificial kidney
Based on the studies of the past and relying on the technology of today, new WAK devices have been developped. 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 North American FDA and European CE approved standards), that a truly wearable device is now possible.
We have recently reported our experience with both a wearable ultrafiltration device , and also a wearable artificial kidney . Patients were filmed in both trials to show that they could walk and move around independently, whilst still being treated, and in one of the studies patients walked out from the hospital, into a neighbouring park, whilst being treated.
Thus, although we would not claim any originality to the concept of a wearable hemofilter 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 whilst being treated. As such, these are landmark proof of concept studies (31-33).
The WUF: The number of patients with symptomatic congestive heart failure continues to increase in North American and Europe. As cardiac output falls, the natural compensatory response to arterial underfilling is an increase neuro-hormonal activation, which paradoxically can lead to further reduction in cardiac output, compromising renal and gut blood flow . 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 fluid retention states, refractory to diuretic therapy . In the early 1980s Kramer, and colleagues described a simple ultrafiltration device, designed to remove fluid from fluid overloaded intensive care patients . This required arterial access, which drove the flow through the hemofilter by hydrostatic pressure, leading to ultrafiltration. However it took more than 25 years before specific devices designed for ultrafiltration of patients with refractory heart failure were available . 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, whilst being treated, and so offer the possibility of outpatient therapy, other workers pursued Kramer's original concept . To allow mobility, patients required a dual lumen central venous access catheter, coupled to a miniaturized blood pump, with accurate battery powered mini-pumps to regulate the ultrafiltration flow, and a heparin infusion for anticoagulation . A standard commercially available high flux polysulfone hemofilter (Medica, Medolla, Italy) was strapped to a belt, which was worn around the waist. The total weight of the device was 2.5 lbs (1.135 kg). The first human study using this wearable hemofiltration device as a continuous ambulatory ultrafiltration device was recently reported , with six volume overloaded patients treated for 6 hours. Blood flow through the device was around 116 ml/min with an ultrafiltration 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. As one of the main problems with traditional intermittent hemodialysis treatments, is intradialytic hypotension, which may cause further ischemic renal injury . Thus, this device by being designed to operate continuously, can remove fluid at a slower hourly rate, compared to standard intermittent hemodialysis, such that refilling of the plasma volume from the extravascular spaces can be maintained, so 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 underfilling, so 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 haemodialysis device . In this preliminary trial, the device was worn by eight chronic haemodialysis 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 ultrafiltration pump, and as with a conventional haemodialysis machine, there were safety features to stop blood flow in case or air entry, or disconnection. The device was connected using the patient's standard vascular access, so via fistula 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 haemodialysis machine, would have continued to pump, with this device, the arterial disconnect was sensed, and the blood pump stopped. This allowed almost immediate re-insertion of the dialysis needle, with no significant loss of blood, and the treatment promptly resumed. In two cases, as the heparin infusion was reduced, prior to the planned termination of treatment, clotting occurred. Thus, as with standard intermittent haemodialysis, adequate anticoagulation is required for this device.
The dialysate was continuously regenerated by passage through three 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 flows were much slower, than traditional thrice weekly intermittent haemodialysis, being 59 and 47 ml/min, respectively. As expected, minute by minute small solute clearances were also much lower than those of intermittent haemodialysis, with an average whole blood urea clearance of 23 ml/min and creatinine clearance of 21 ml/min respectively. Although these minute by minute clearances are low, and similar to those achieved by continuous arterio-venous dialysis circuits in the intensive care setting , the device was designed to be worn for protracted periods. If this wearable haemodialysis device could be worn daily, then this would potentially provide an estimated urea clearance (Kt/V) of almost 6.0, well above that for conventional thrice weekly intermittent haemodialysis.
In addition to urea and creatinine clearances, b2 microglobulin clearance was also assessed. b2 microglobulin clearance was some 50% of that of urea and 55% for creatinine, respectively. Recent re-evaluation of the HEMO study, has suggested the importance of 2 microglobulin clearance in predicting patient survival . As the adequacy of haemodialysis 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 haemodialysis. This is probably due to a degree of internal haemodiafiltration within the dialyzer, due to the pressures generated by the blood pump. The blood pump differed in design to that of a conventional haemodialysis machine blood pump, in that instead of being a roller pump, which occluded the dialysate tubing, this blood pump comprised two chambers, one for blood and one 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 flows through the dialyzer compared to standard dialysis, resulting in increased internal haemodiafiltration.
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 flows.
The ViWAK: Recently, the structure and operational characteristics of a new wearable system for continuous peritoneal dialysis for CKD patients have been described in a paper  and called Vicenza wearable artificial kidney (ViWAK). The Viwak system consists of a double lumen peritoneal catheter; a dialysate outflow line; a miniaturized rotary pump; a circuit for dialysate regeneration featuring a water proof container with cartridges connected in parallel with a mixture of activated carbon and and polystyrenic resins; a filter for deaeration and micro-biological safety; a dialysate inflow line; a palm computer as a remote control.
The system has been tested circulating 12 liters of exhausted PD solution through the experimental adsorption unit at the rate of 20 ml/min. Creatinine, Beta 2 microglobulin and Angiogenin were measured before and after the adsorption unit at baseline, and after 4 and 10 hours of use.
The cartridges containing polystirenic resin completely removed beta-2 microglobulin and angiogenin from the fluid batch. Those with the ion exchange resin removed completely urea and creatinine. The final result was 11.2 liters of net solute clearance.
The system is designed to be used as follows: The peritoneal cavity is loaded in the morning with 2 liters of fresh PD solution. After 2 hours, when dialysate/plasma equilibration at 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 ultrafiltration if needed. After 2 hours the fluid is drained and a 2 liters icodextrin exchange is performed overnight to achieve further ultrafiltration. The clearance provided by the minicycler is further increased by the 2 liter exchange and the overnight exchange.
Therefore, the system operates 24h/day and provides creatinine and beta-2 microglobulin clearance in the range of 15 - 16 l/day, corresponding to a weekly clearance of 100-110 liters.
The patient reduces the number of exchanges compared to CAPD and uses less fluid then in APD. Furthermore, the palm pilot allows for prescription and assessment of the therapy providing information on of cartridge saturation, flow and pressure conditions and offering the possibility of remote wireless control of operations. Some problems still remain to be solved in the present configuration including the addition of an injection system for glucose and bicerbonate when needed, a system to reduce fibrin delivery to the sorbent and finally a more complex misture 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 perform exchanges and improving peritoneal dialysis adequacy and patient's rehabilitation.
In conclusion, the wearable artificial kidney is becoming a reality although many improvements may still be required. The change in paradigm may help future development and contributions coming from scientists and industry oriented towards the refinement of the WAK concept. The same concept might be useful to develop new strategies in the treatment of the critically ill patient [51-53]. Miniaturization and non thrombogenic surfaces will probably represent the most important challenges for the immediate future. Nevertheless, the future in this field is probably tomorrow.
Prof. Claudio Ronco
Director Dep. Nephrology Dialysis & Transplantation San Bortolo Hospital – Vicenza
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