Portable and wearable dialysis: where are we now?

From http://onlinelibrary.wiley.com/doi/10.1111/j.1542-4758.2010.00486.x/abstract

DAVENPORT, A., RONCO, C. and GURA, V. (2010), Portable and wearable dialysis: where are we now?. Hemodialysis International, 14: S22–S26. doi: 10.1111/j.1542-4758.2010.00486.x

Although dialysis is a life-saving treatment for patients with acute and chronic kidney disease, mortality remains high, with the survival of patients treated by regular hemodialysis similar to that of some solid organ tumors. Recent reports have suggested that a major increase in the dose of dialysis, delivered by frequent nocturnal dialysis, may improve survival. Unfortunately, only a minority of centers can offer this type of therapy, and only to a minority of their patients. Thus, to improve access to dialysis as well as increase the delivered dose of dialysis, a major change in the current paradigm of dialysis delivery is required. For many years, the “holy grail” of dialysis has been to develop a wearable or portable system, allowing patients to be treated while performing their normal activities of daily living. It is only recently with the advances in technology that such dialysis devices have been possible. Prototype devices for both hemodialysis and peritoneal dialysis have been studied with favorable results. Typically, these have been short-term studies, and longer term trials are eagerly awaited, to determine whether the current generation of wearable continuous dialysis devices cannot only remove waste products of metabolism and control volume but also maintain acid-base and electrolyte homeostasis and actually improve outcomes. In addition, a novel generation of dialysis devices based on nanotechnologies are being developed. Hopefully, these wearable continuous devices will be available as an option for routine clinical practice in the not-too-distant future.

Introduction
Although there have been major technological advances in both hemodialysis and peritoneal dialysis over the past 60 years, the mortality of patients with chronic kidney disease remains disappointingly high, greater than that of some solid organ tumors. As patients progress to end-stage kidney disease, nitrogenous products of metabolism accumulate the so-called azotemic toxins. Traditionally, urea has been used as a marker of these azotemic toxins, as it can be readily and reliably measured. In plasma, urea can dissociate to form cyanate, which can then react with proteins and lipids to form carbamylated products.1 Although there are similarities to glycosylation found in diabetic subjects, these reactions are reversible rather than forming an irreversible Amadori product. Thus, regular dialysis can control carbamylation,2 and prevent urea accumulation and toxicity. Clinical studies have reported that above a critical threshold of urea clearance, short-term survival was not improved by a 20% increase in dialysis dose.3 However, for patients established on dialysis the accumulation of the so-called middle molecules over time becomes a risk factor for reduced survival.4 Middle molecules and small protein-bound hydrophilic and lipid solutes are only slowly removed during a dialysis session, and therefore increase over time when patients are dialyzed to achieve urea-based targets. As urea clearances are over estimated in small patients and women, and conversely under estimated in the obese,5 this leads to an increased accumulation of these toxins in the smaller patient and women, but better clearances for the obese. This practice leads to chronic under dialysis of the small person and women with an increased mortality, and a better survival for the grossly obese patient, thus helping to explain this apparent paradox.6

To remove these toxins, patients require more dialysis, either more frequent sessions, or preferably longer session times. Although nocturnal hemodialysis is potentially available for home dialysis patients, only a small number of dialysis facilities are currently available to offer this facility, and even that too, to only a minority of patients. Thus, to enable more patients to benefit from additional time on dialysis, a new approach to treatment is required. One such strategy would be to provide continuous treatment, which would have to be not only wearable but also allow patients to continue with their daily activities to allow continuous treatment.

Portable dialysis - the early years
The first advance to developing a wearable hemodialysis device was the introduction of a portable dialysis system that allowed the patient to travel.7 These pioneering devices used a batch dialysate system, with the spent dialysate regenerated by a charcoal module, coupled with rechargeable batteries.8 These devices were somewhat heavy, mainly due to the batteries and blood and dialysate pumps.9 Despite the enthusiasm for portable hemodialysis,10 these devices were abandoned, due to the technical problems of reducing size and weight.11 However, the interest in sorbents led to the development of commercially available sorbent-based dialysis, the Reddy® system (SORB Technology Inc., Oklahoma City, OK, USA), which allowed patients to go on holiday and dialyze outside dialysis centers.

The next generation of portable devices was based on hemofiltration, allowing continuous ultrafiltration,12 using an arterio-venous shunt (either a wrist Scribner shunt or a femoral access Thomas shunt), for access, and a simple gate clamp to control ultrafiltration. To allow clearance of azotemic toxins, spent ultrafiltrate was regenerated by sorbent cartridges, and returned to the patient.13 The sorbent cartridges were quickly saturated and had to be changed several times a day. Owing to the technological challenges, little progress was made until recently.

Wearable peritoneal dialysis devices
Peritoneal dialysis on the other hand moved forward in leaps and bounds from an intermittent treatment using hard catheters with glass bottles of dialysate, to a truly wearable dialysis system by the late 1970s, using silicone catheters and disposable dialysate bags. Infection was, and remains the main complication of peritoneal dialysis,14 although infection rates have fallen with the introduction of flush before fill techniques, and topical exit site antibiotics. Despite an effective dialysis technique, particularly for patients with some residual renal function, peritoneal dialysis programs continue to have a very high turnover of patients, with patients transferring to hemodialysis following peritonitis, ultrafiltration failure, and inadequate solute clearances. In addition, there are increasing concerns of encapsulating peritoneal sclerosis with a longer term treatment.15

Although peritoneal dialysis is a wearable and portable form of dialysis, patients either require a cycler machine, or perform several daytime manual exchanges. To allow patients freedom from daytime exchanges or overnight machines, several attempts have been made to develop a sorbent-based system to regenerate spent dialysate.16,17 This could be performed by 2 separate peritoneal dialysis catheters, or a single coaxial design, with a battery-operated pump designed to pump the dialysate into and out of the peritoneal cavity, with an additional pump to regulate ultrafiltration (Figure 1). On the one hand, these devices offer a relatively simple design and concept, but on the other, over time the solutes used to generate osmotic gradients are absorbed. The question then arises as to how to best renew or refresh the dialysate, by adding electrolytes, buffer base, and osmotic agents.

(Figure 1 missing here)

Wearable hemodialysis devices
To develop a wearable and truly portable hemodialysis device, several key hurdles had to be overcome, ranging from the novel design of a battery-operated, light-weight, but powerful blood and dialysate pumps coupled with light-weight sorbents, additional pumps to regulate acid-base and electrolyte balance, and with appropriate safety mechanisms.18 Recently, such a device has been created, and shown to effectively allow controlled ultrafiltration,19 and also dialysis.20 Small solute clearances being similar to those obtained with continuous therapies in the intensive care unit,20 but with greater middle-sized molecule clearances due to the combination of convective transport induced by the double channel push-pull blood and dialysate pump in opposite phase21 coupled with adsorption by the sorbents.22 Although the early trials of this device were very encouraging, several problems were highlighted, including the formation of carbon dioxide gas bubbles, reliance on anticoagulation and vascular access.23 The experiences and information gained from the initial pilot trials resulted in technical design improvements, eliminating gaseous bubbles by utilizing gas-permeable plastics, and extracorporeal circuit redesign to reduce anticoagulation requirements.24 In addition, safety improvements were made by placing the sorbent cartridges and the pumps regulating electrolyte, pH, and anticoagulation, in a casing both designed to not only withstand trauma but also body contoured to improve wearability. Modifications of blood and dialyzer pump, and some of the other components reduced not only the size of the device but also the weight, down to about 5 lbs (Figure 2).

(Figure 2 missing here)

Other groups have also been working on developing a wearable hemodialysis device, including implantable nanotechnology devices using a highly permeable dialyzer membrane allowing the filtration of albumin and plasma solutes, which can then be adsorbed using a series of sorbents (nanoclay, hydrotalcite, nanoporous carbon, and nanoporous polymer) designed to remove both plasma solutes and protein bound toxins.25

The future
The advances in computer chip technology have allowed the creation of battery-powered miniaturized pumps, coupled with feed back loops, which underpin the resurgence of interest in developing truly portable and wearable dialysis devices. Phase 1 and phase 2 trials have been undertaken with a hemodialysis device. These trials have typically been short term26 and therefore need to be extended before these devices can truly be considered as continuous wearable modes of dialysis and be introduced into every day clinical practice. Renal replacement therapies should not just remove waste products of metabolism and volume control, but should also correct acid-base imbalances and maintain electrolyte homeostasis. The current generation of wearable devices have shown encouraging results in terms of solute clearances and volume control,27 but have yet to be shown to control acid-base and electrolytes in the longer term.

Summary
The early pioneers of dialysis need to be congratulated for their sterling efforts to develop dialysis from a highly specialized treatment, limited to a few patients treated in a small number of university associated hospitals, to a treatment now available world wide to an ever expanding number of patients, often now dialyzing in free standing dialysis centers or at home. The early pioneers recognized the limitations of dialysis on life style and quality of life for patients. Thus, the “holy grail” even more than 30 years ago was to develop a portable or wearable dialysis device. It is only recently with the advances in technology that there has been a resurgence of interest to develop wearable continuous hemodialysis and peritoneal dialysis devices. The initial phase 1 and 2 trials have been encouraging, and the results of longer term trials are awaited with enthusiasm to determine whether the current generation of devices can truly be considered effective alternatives to current hemodialysis and peritoneal dialysis techniques. In addition, several groups are working on nanotechnology devices designed to be implanted or attached to the skin, providing a potential new generation of novel therapies. Thus, it is anticipated that wearable continuous dialysis devices will enter every-day clinical practice within the decade.

Acknowledgement
Conflicts of interest: Victor Gura receives a salary from Xcorporeal Inc.

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