Alternative chronic kidney replacement therapies

INTRODUCTION — 

To address current shortcomings of existing chronic kidney replacement therapy (KRT) modalities, new and innovative forms of KRT are emerging, primarily in the form of wearable devices [1]. These and other alternative approaches to chronic KRT are discussed in this topic review. Established alternatives to conventional in-center hemodialysis (ie, home dialysis and in-center hemodiafiltration) are discussed separately:

●(See "Evaluating patients for chronic peritoneal dialysis and selection of modality".)

●(See "Prescribing peritoneal dialysis".)

●(See "Choosing home hemodialysis for end-stage kidney disease".)

●(See "Technical aspects of nocturnal hemodialysis".)

●(See "Outcomes associated with nocturnal hemodialysis".)

●(See "Short daily hemodialysis".)

●(See "Short daily home hemodialysis: The low dialysate volume approach".)

●(See "Prescribing chronic intermittent high-volume hemodiafiltration".)

●(See "Outcomes associated with chronic hemodiafiltration".)

RATIONALE FOR NEW KIDNEY REPLACEMENT THERAPIES — 

New forms of kidney replacement therapy (KRT) are being developed to address shortcomings of existing chronic KRT modalities. Despite improvements in KRT technologies and general medical care, the outcomes and experience of patients undergoing chronic KRT remains suboptimal and falls dramatically short in approximating the function of healthy native kidneys [2].

Though it is the most ubiquitous form of chronic KRT, conventional in-center hemodialysis has many shortcomings impacting patient physiology, clinical outcomes, and quality of life. Due to its intermittent nature and relatively constrained treatment time, in-center hemodialysis is often complicated by suboptimal fluid and solute removal as well as cyclical fluid overload and intradialytic hypotension, contributing to significant morbidity and mortality. Moreover, facility-based modalities in general place significant burdens on patients and their families with confinement to a fixed schedule, inability to travel, and restricting work and leisure activities.

Home dialysis modalities can help to overcome many but not all these challenges. Both home hemodialysis and peritoneal dialysis enable a more personalized approach to treatment scheduling, diet, and other treatment parameters that can improve physical health and quality of life. However, there are several barriers to home dialysis uptake and long-term success (see "Home hemodialysis (HHD): Establishment of a program"). Moreover, although home hemodialysis and peritoneal dialysis devices have become more portable in recent years, the devices themselves along with dialysis supplies (including premixed dialysate bags) are not easily transportable and continue to restrict patient mobility and spontaneous travel.

AMBULATORY DIALYSIS — 

Ambulatory kidney replacement therapy (KRT) modalities are based on wearable or implantable devices. To date, none of these devices have been approved for clinical use by the US Food and Drug Administration (FDA). Wearable artificial kidneys have been developed for hemodialysis and peritoneal dialysis, while implantable devices have focused primarily on a hemodialysis-based approach.

Optimal design features — Design features central to all ambulatory KRT modalities include the following:

●Portability – A primary design feature in all ambulatory KRT devices is portability, enabling freedom of movement with minimal interference in a patient’s personal and professional activities.

●Extended treatment times – Since miniaturization of the dialysis apparatus generally reduces treatment efficiency, ambulatory KRT will invariably require longer or more frequent treatment, further underscoring the need for devices that are relatively light weight, ergonomic, comfortable, and even discrete enough to wear under normal clothing, while safely providing sufficient fluid and solute removal.

●Ease of operation – For ambulatory KRT to be successful, it must be relatively easy to teach, learn, and perform.

Patient preference — For ambulatory dialysis technologies to be widely adopted, patients must endorse them. Patient surveys suggest that many patients would tolerate substantial safety risks in exchange for the freedom and mobility provided by ambulatory dialysis devices [3]. However, there may be substantial between-person variation in the preferred design characteristics of wearable dialysis devices [4]. Furthermore, it is unclear whether a wearable dialysis system would be preferable to unwearable dialysis devices that are lighter, smaller, and more portable than current devices used for existing home KRT modalities.

Wearable hemodialysis systems — Several wearable hemodialysis systems, also known as a wearable artificial kidney (WAK), have been developed over the past few decades, although none have been used commercially. A typical WAK is a battery-operated device that is worn as a belt [5-8]; prototypes have weighed anywhere from approximately two to ten pounds. Using a hollow fiber dialyzer, dialysate is continuously regenerated by a sorbent-containing adsorption cartridge, generally based on the REDY (Recirculation of DialYsate) system in a miniaturized form (see 'Dialysate regeneration' below). In a pilot study, eight patients with ESKD who wore a hemodialysis WAK for four to eight hours had a mean plasma urea and creatinine clearance rate of 23 and 21 mL/min, respectively [6]. The device was well tolerated, but clotting of the circuit was noted in two patients [8].

Wearable peritoneal dialysis systems — A wearable artificial kidney for peritoneal dialysis (WAK PD) has been developed that uses sorbents to regenerate peritoneal dialysis fluid. The WAK PD is a tidal dialysis system with a tidal volume of 500 mL; the drained dialysate is pumped through a sorbent cartridge, filtered, degassed, and supplemented with electrolytes and glucose before it is returned into the peritoneal cavity. WAK PD performs eight exchanges per hour, delivering a urea clearance of approximately 30 mL/min. Its cartridge needs to be replaced every seven hours [9,10].

Implantable bioartifical kidney — The implantable bioartificial kidney is an experimental technology that incorporates tissue engineering [11]. The original form, which was called a “renal tubule assist device,” consisted of immortalized proximal tubular cells cultured on the luminal side of a hollow fiber dialyzer inserted in series with a conventional continuous veno-venous hemodiafiltration circuit. An initial study in critically-ill patients with acute kidney injury showed some promise with improved cytokine profiles but identified logistical challenges with cell viability, storage, and distribution [12]. This led to the development of the Bioartificial Renal Epithelial Cell System (BRECS) [13], which is comprised of renal epithelial cells cultured on niobium-coated carbon disks mounted in a perfused housing. The potential use of this “bioreactor” has evolved and is now a core component of implantable artificial kidney prototypes; it will be used in combination with a silicon-based hemofilter without the need for a mechanical pump [14]. (See 'Blood pump' below.)

TECHNICAL REQUIREMENTS FOR WEARABLE HEMODIALYSIS — 

The key components of a wearable hemodialyzer include vascular access, blood pump, dialysate regeneration, dialysis membrane, and ideally, a patient monitoring system. A summary of key requirements and recent innovations for each of these components follows [15]:

Vascular access — In addition to the usual risks of clotting, infection, and air embolism, vascular access for ambulatory hemodialysis poses unique challenges. In contrast to patients treated with a conventional hemodialysis machine while seated or supine, ambulatory patients engaged in activities of daily living are likely at a much higher risk of needle dislodgement, with potentially serious consequences. To mitigate this risk, proposed arteriovenous access approaches have included:

●Implantable vascular access devices with needle-locking mechanisms

●Implantable grafts made of novel materials (bioengineered or otherwise) [16,17]

●Single needle cannulation (borrowed from home hemodialysis) to limit blood loss in the event of an accidental dislodgement

While catheters are often considered inferior to AV access due to infection risk and thrombotic occlusion, they may represent a more practical alternative for safely administering ambulatory hemodialysis. The relatively low blood flow rates used with ambulatory hemodialysis would be expected to increase the risk of thrombosis, but new innovations in biocompatibility and catheter design to promote laminar flow could help overcome this barrier. Additionally, novel catheter caps and antibiotic catheter lock solutions for central venous catheters may mitigate some of the excess infectious risk conferred by long-term catheter use in patients undergoing ambulatory dialysis [18,19]. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention".)

Blood pump — A number of prototype wearable hemodialysis devices have used a pulsatile flow pump driving both blood and dialysis simultaneously to avoid the need for multiple fluid pumps [6]. Key design features for enabling ambulatory hemodialysis include compact and lightweight design, energy efficiency, a reliable power source of adequate capacity, minimal heat generation, and the ability to support adequate blood flow rates without damaging the cellular elements of circulating blood. (See 'Optimal design features' above.)

Dialysate regeneration — In contrast to conventional single-pass hemodialysis, which requires a constant infusion of new dialysate to remove solutes, ambulatory hemodialyzers regenerate spent dialysate using sorbents and enzyme technologies. Currently available dialysate regeneration systems remove organic molecules as small as creatinine and as large as middle molecules through activated carbon adsorption, and include ion-exchange cartridges containing zirconium-based compounds to remove potassium and phosphorus.

One key challenge for the development of a dialysate regeneration system in ambulatory hemodialysis has been the management of the daily urea load generated from the metabolism of proteins and other nitrogen-containing compounds in the body. Although its role as a uremia toxin is uncertain, urea represents a major nitrogen-containing compound circulating in the blood and is produced in quantities which approach 50 grams per day in humans. The most common method used to remove the daily urea load in wearable dialysis prototypes has been the insertion of urease-containing cartridges in series with sorbent-containing cartridges. The REDY (Recirculation of DialYsate) system first developed in the 1970s was the first portable system to couple urea removal with regeneration of dialysate using sorbent technologies, but ultimately was abandoned due to aluminum leaching and the high cost of sorbent materials that needed to be replaced with each dialysis treatment. A further challenge with the enzymatic degradation of urea in sorbent-based ambulatory dialysis systems is the generation of carbon dioxide gas, which has proved challenging to manage in prototype devices [20].

A variety of nonenzymatic methods of urea degradation have also been reported, though none yet used successfully in human studies of ambulatory dialysis devices. Such novel methods have generally relied on electrochemical decomposition of urea by conversion into nitrogen, water, and carbon dioxide gas using miniature electrode modules [21]. More recently, photochemical decomposition of urea has also been attempted, although production of toxic compounds such as chlorine species has complicated this approach [22].

Dialysis membranes — The limitations of conventional high-flux dialysis membranes are likely to be exacerbated by the typical treatment parameters required for ambulatory kidney replacement therapy (KRT). The thrombogenicity of contemporary polymeric dialysis membranes, which reflects imperfect biocompatibility and requires circuit anticoagulation in conventional hemodialysis, presents a greater challenge in the context of low blood flow ambulatory hemodialysis. In addition to their thrombogenicity, contemporary dialysis membranes are prone to fouling due to protein adsorption, which tends to worsen over time and could be especially problematic with the longer duration of therapy typical in ambulatory KRT. Finally, the clearance of larger middle-molecules, which is already a concern with conventional hemodialysis, is further limited by the low blood flow of ambulatory KRT.

These challenges have given rise to new approaches to membrane fabrication and materials, leveraging nanotechnology to further enhance biocompatibility, blood flow, and patency, while expanding the range and quantity of uremic solutes removed. Some recent innovations in membrane technologies and their main attributes include:

●Modified polymeric membranes – Most commercially available membranes in use are based on hydrophobic polymers (eg, polysulfone and related materials), coated with hydrophilic compounds (eg, polyvinylpyrrolidone) that improve biocompatibility but can potentially leach with prolonged use. Grafting of hydrophilic additives such as polyvinyl alcohol with chitosan to improve biocompatibility or grafting of argatroban (a direct thrombin inhibitor) to reduce thrombogenicity may extend the duration of membrane performance. However, the relatively high hydraulic resistance of polymeric membranes may limit the degree of miniaturization that is currently feasible with the blood pumps required to drive them [23].

●Silicon-based membranes – Silicon-based nanoporous membranes can be precision-engineered to provide lower hydraulic resistance with more uniform and highly-tunable pore sizes. However, owing to the poor biocompatibility of silicone with human blood, polyethylene glycol or other coatings are needed to limit protein adsorption and thrombosis. Preliminary animal studies suggest that a miniaturized (0.17m² surface area; 10-fold smaller than a conventional dialyzer) coated silicon nanopore membrane could provide adequate urea clearance for up to a month in pigs dialyzed for 7 hours, thrice weekly in an implanted bioartificial kidney driven only by the arterio-venous pressure differential with no need for a separate blood pump [24].

●Mixed matrix membranes – Mixed matrix membranes combine a hemocompatible inner porous polymeric layer with an outer layer impregnated with activated charcoal. This design could enable adsorptive clearance of various uremic toxins, including protein-bound solutes, while reducing the volume of dialysate required in ambulatory KRT [25].

Patient and treatment monitoring — The safe administration of ambulatory hemodialysis requires real-time monitoring and an alert-response system to detect air and blood leaks, blood and dialysis flow deviations, vital signs, and other parameters. Cloud-based monitoring systems developed for home hemodialysis could serve as a jumping off point for developing further miniaturized telemetry systems for ambulatory hemodialysis with electronic medical record (EMR) integration.

SUMMARY

●Overview – Despite improvements in kidney replacement therapy (KRT) technologies, the outcomes and experience of patients undergoing chronic KRT remains suboptimal and falls dramatically short in approximating the function of healthy native kidneys. To address current shortcomings of existing chronic kidney KRT modalities, new and innovative forms of KRT are emerging. (See 'Introduction' above and 'Rationale for new kidney replacement therapies' above.)

●Ambulatory dialysis – Ambulatory KRT modalities are based on wearable or implantable devices. Wearable artificial kidneys have been developed for hemodialysis and peritoneal dialysis, while implantable devices have focused primarily on a hemodialysis-based approach. Optimal design features of all ambulatory KRT modalities include portability, extended treatment time, and ease of operation. (See 'Ambulatory dialysis' above.)

●Technical requirements for wearable hemodialysis – The key components of a wearable hemodialyzer include vascular access, blood pump, dialysate regeneration, dialysis membrane, and ideally, a patient monitoring system. (See 'Technical requirements for wearable hemodialysis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Andreas Pierratos, MD, FRCPC, who contributed to earlier versions of this topic review.