Selection Committee Member: Bill Fissell @fisselliv
William H. Fissell is a physician-scientist, nephrologist, and an Associate Professor of Medicine and Biomedical Engineering within Vanderbilt University School of Medicine and Vanderbilt University. While in medical residency, he was appalled by the dismal options available to patients with renal failure and decided to apply his undergraduate experience in nanotechnology to unmet needs in nephrology. He is past president of the American Society for Artificial Internal Organs and Medical Director of The Kidney Project, an interdisciplinary multicenter project to develop a biohybrid implantable artificial kidney.
Writer: Krishna Agarwal @KrishnaAdit
Krishna Agarwal is a nephrology fellow at Beth Israel Deaconess Medical Center. He is originally from Delhi, India, where he completed medical school at Vardhman Mahavir Medical College. He moved to Boston in 2014 to pursue a Research Fellowship in Prof. Terry Strom’s Immunology lab at Harvard and then internal medicine residency at Baystate Medical Center in Western Massachusetts. His ultimate clinical interest lies in transplant nephrology with a research focus in long-term allograft survival and transplant tolerance. He is a current AJKD Editorial Intern.
Competitors for the Artificial Kidney Region
Kidney replacement therapy has made nephrology a clinical specialty, allowing us to move beyond physiology and disorders of water and acid-base. At the same time, the main advances in dialysis care over the last half century have primarily been pharmacologic (eg erythropoietin, vitamin D, binders, etc.) rather than in kidney replacement therapy itself.
Based on the United States Renal Data System, more than 800,000 people have end-stage kidney disease in the United States and, of those, approximately 550,000 depend on maintenance dialysis. The five-year survival rate for dialysis-dependent individuals is less than 50%. Medicare spending for the overall care of hemodialysis (HD) dependent patients was close to $29 billion in 2018. Despite these staggering numbers, not much has changed in dialysis technology since the advent of hollow fiber dialyzers in the 1960s.
Trials of frequent dialysis (such as the The Frequent Hemodialysis Network data) have shown that more frequent HD, mimicking the continuous function of kidneys, has benefits. These include: 1) reduction in the left ventricular mass, 2) better volume management, 3) improved physical and (and arguably mental) health-related quality of life, 4) shortened post-dialysis recovery time, 5) improved blood pressure control, and 6) reduced need for phosphorus binders and hence, reduced pill burden. Some of these also may be achieved by a more continuous form of dialysis – peritoneal dialysis (PD). But there are limitations to PD, including variable clearance of small solutes resulting in dependence on residual kidney function, significantly time-consuming setup, metabolic consequences of glucose loading, and risk of peritonitis. Frequent HD also comes with an increased risk of access interventions. Therefore, both conventional HD and PD are limited by overall poor clinical outcomes, lack of mobility, high morbidity and mortality, and high costs.
To overcome the limitations of these conventional modalities, research has been ongoing to develop wearable or implantable artificial kidneys that provide a more continuous and physiologic dialysis, thereby mimicking the human kidney. This has been aided by advances in nanotechnology, microfluidics, and biomaterials. This region matches up several of the candidate devices currently in development.
WAK – Wearable HD vs AWAK – Wearable PD
WAK – Wearable HD
Let’s just get it out of the way: the acronyms all suck. The wearable artificial kidney (or WAK) is just a mini hemodialysis machine. It’s small (relatively), it reuses dialysate, and you wear it around like a fanny pack. Is this the future, or are there other teams in this region that can supplant this technology?
Conventional HD and PD therapies are water-voracious. For example, a typical HD treatment uses at least 120 liters of dialysate for a 4-hour treatment session. Approximately 300-500 liters of water are needed to generate this dialysate through reverse osmosis. Water treatment units are expensive, high-maintenance, and not eco-friendly (see the Green Nephrology region from last year on consumable waste in dialysis). Moreover, adapting a similar process to the home requires additional plumbing and electrical wiring, thus limiting its portability. Similarly, PD patients use anywhere from 8-12 liters of pre-manufactured dialysate fluid every day, and traveling requires considerable forethought and planning.
Utilizing water in an efficient and recyclable way is crucial to achieving a wearable dialysis machine. This has been achieved by the regeneration of a small volume of dialysate by enzymatic degradation of urea into ammonia, on exchange columns, and charcoal-based adsorption. The first system to employ such a sorbent system was the REcirculating DialYsate (REDY) dialysis system. Essentially, the spent dialysate passes through a chamber containing immobilized urease which hydrolyzes urea into ammonium and bicarbonate. From there, it passes through a cation exchanger which binds calcium, magnesium, and potassium in exchange for sodium and hydrogen, and an anion exchanger which binds phosphate in exchange for hydroxide, bicarbonate, and acetate anions. The last step before regeneration involves an activated charcoal chamber which binds non-urea organic compounds. From here, dialysate regeneration involves reconstituting the purified dialysate with essential cations—like calcium, magnesium, and potassium—for the next cycle.
The major advantage of the REDY system was portability (its initial weight was approximately 20 kg) and hence it was used to successfully perform more than six million dialysis treatments between 1973 and 1994 on floors, ICUs and other non-dialysis units in the hospital. Unfortunately, manufacturing of the REDY system was discontinued in 1994 due to the high cost of disposable cartridges, inferior treatment adequacy as compared to the fixed reverse osmosis-generated dialysate, and aluminum-induced toxicities like osteomalacia and dementia (which was attributed to aluminum contamination of the activated charcoal used in this system). Other issues with this system included release of sodium in exchange for cations which led to high interdialytic weight gain and hypertension, excessive ammonium production which required a relatively large amount of zirconium phosphate to remove it, and removal of calcium, magnesium, and potassium, requiring replenishment via separate reservoir.
Since the discontinuation of the REDY sorbent system, several researchers have been working on second generation urease-based sorbent systems. One of these is the Wearable Artificial Kidney (WAK). This is a blood-based, battery-powered, wearable kidney replacement system that weighs approximately 5 kg. Subsequent generation designs are thought to be lighter, but have not been made public at this time. The WAK only requires 375 mL of dialysate, which is regenerated and recirculated. It utilizes heparin to anticoagulate blood, which is drawn from and returned to the body via a double-lumen central venous catheter. The battery-powered pump runs blood and dialysate using push and pull pulses through a hollow fiber filter. The flow is such that the blood flow peaks when the dialysate flow ebbs, and vice versa. This innovative pulsatile push-pull mechanism allows for adequate clearances with relatively low blood flows, in the range of 100 mL/min. In their first trial, conducted in pigs with kidney failure, Gura et al demonstrated an effective urea clearance of 37.0 ± 7.3 mL/min, a creatinine clearance of 27.0 ± 4.0 mL/min, and an hourly Kt/V of 0.045 ± 0.002. A proof-of-concept trial involving 8 HD patients showed that the WAK was also able to remove middle molecule uremic toxins like beta-2 microglobulin with a mean clearance of 11.3 ± 2.3 mL/min. Traditional high flux HD can remove closer to 50 mL/min of beta-2 microglobulin, but does not provide the continuous 24-hour-a-day clearance offered by the WAK. Similarly, clearance of inorganic phosphate was 21.7 ± 4.5 mL/min, which has the potential to eliminate the need for phosphorus binders.
There are certain disadvantages to the WAK system. First, the long term exposure to the extracorporeal circuit of the WAK system may have inherent immunologic activation due to continuous blood-artificial membrane interactions. Second, enzymatic degradation of urea by urease produces carbon dioxide bubbles which can impede the dialysate flow. This has been managed to some extent by using gas-permeable tubing. Third, clotting of the venous catheter due to slow blood flow rates is a serious potential problem. Systemic heparin was used in preliminary clinical trials to overcome this problem. Fourth, with any wearable device, dislodgement of the needle(s) from the bloodstream is a major drawback with potential for significant blood loss. This may mean that the WAK devices will more commonly use catheters in place of fistulas. Finally, the sorbents used for dialysate regeneration need frequent replacement and that may limit actual “wearability”.
Despite these drawbacks, this product has already been tested in humans, and essentially functions as a mini-continuous HD device. If we can make the same progress that led from Kolff dialyzers to today’s filters, this team may achieve dominance on the court.
AWAK – Wearable PD
The automated wearable artificial kidney (AWAK) is a tiny peritoneal dialysis device. It fills and drains about a liter of dialysate into your peritoneal cavity and regenerates and replenishes it before the rinse and repeat. In some ways, this team holds a lot of promise, but how close are they to actually competing?
If the WAK is a miniaturized HD device, the automated wearable artificial kidney (AWAK) is basically a miniaturized PD device (AWAK-PD). It is a continuous system involving tidal dialysate exchanges and employing dialysate regeneration to limit fluid requirements. The first step involves instilling 1-1.5L of dialysate into the peritoneal cavity. This absorbs toxins, waste products, and extra fluid through the peritoneal membrane. Of the initial 1-1.5L, 500 mL is drained from the peritoneum into the storage unit of the AWAK-PD, where it undergoes regeneration through a modified REDY sorbent system (as described above). The regenerated dialysate is then filtered, degassed, and replenished with potassium, calcium, magnesium, and glucose before being returned to the patient. The extra fluid (ultrafiltrate) is routed to a separate bag which can be discarded with the sorbent cartridge, or can alternatively be routed to the urinary bladder. The machine performs 8 exchanges every hour, for a cumulative dialysate flow of 96 L/day. Each sorbent cartridge lasts for 7 hours. A proof-of-concept trial involving 20 male participants reported results of 90 successful PD sessions using the AWAK system. A urea clearance of 31.5 +/- 1.5 mL/min was achieved, and a single patient was maintained on this system for 2 months.
Advantages of peritoneal-based AWAK include: 1) the lack of immunologic and/or non-immunologic effects of blood-artificial membrane interaction, 2) tidal exchanges which eliminate the pain associated with filling and emptying phases of conventional PD, 3) the elimination of albumin loss by recycling dialysate and hence peritoneal proteins, and 4) enhanced middle molecule toxin removal as compared to conventional PD.
Despite these promising benefits, challenges remain with AWAK-PD. Most importantly, as with all sorbent systems, the sorbent cartridge needs to be replaced every 4-8 hours along with the battery and electrolyte replenishment unit. If the bladder is used as an ultrafiltrate reservoir, then patients will need to urinate more frequently. As with conventional PD, the peritoneal membrane could eventually fail. While peritonitis is possible, the incidence in early data based on very small numbers was lower than conventional PD because of decreased need of manipulation, connection-disconnection, and the sterile recirculating dialysate.
The matchup on this side of the bracket showcases the two teams that are most ready for primetime, and it wouldn’t be surprising to see either in the championship game. Both have successful proof-of-concept animal and human models, and similar challenges to their full-size counterparts. If we can get past the confusing WAK/AWAK terminology, and instead consider these to be continuous portable versions of HD and PD, then these artificial kidney therapies may become tangible possibilities in the not-too-distant future!
|Wearable artificial kidney (WAK)||HD||Clinical trials||Victor Gura MD/Blood Purification Technologies Inc.|
|Automated Wearable Artificial Kidney Peritoneal Dialysis System (AWAK)||PD||Clinical trials||AWAK Technologies|
Miniature hemo- and peritoneal- based dialysis machines.
Implantable Bioartificial Kidney vs Scaffolded Bioartificial Kidney
While significant advances have been made in the miniaturization of hemofiltration modalities, none of these devices truly can mimic the human kidney. The ultimate goal of developing an artificial kidney is an implantable, self-monitoring, programmable device that not only balances fluids and electrolytes but also performs the many metabolic, endocrine and immunologic functions of the kidneys. Recent developments in microelectromechanical systems (MEMS), nanotechnology and stem cell technology have aided progress in this field.
David Humes and colleagues developed the Renal Assist Device (RAD), the first bioartificial kidney, in 1997. This device consisted of porcine renal proximal tubule cells grown in confluent monolayers along the luminal surface of hollow fiber membranes in a multifiber bioreactor with a membrane surface area of 0.4-1.6 m2. The RAD was able to transport sodium, glucose, and PAH across the artificial membrane; ammoniagenesis, gluconeogenesis, and glutathione synthesis were observed, IL-10 was produced, and vitamin D was activated. In preliminary experiments in uremic dogs, the RAD was compared with a sham device placed in an extracorporeal continuous hemoperfusion circuit in series with a traditional continuous renal replacement therapy hemofilter. The RAD-treated group showed significant reduction in plasma potassium and urea levels, ammonia excretion in processed filtrate, glutathione reclamation, and increased plasma 1,25-dihydroxy vitamin D levels. In 2003, Dr. Humes’ group published the results of a large animal study specifically looking at the effects of the RAD in sepsis-induced acute kidney injury. Nephrectomized dogs (with E. coli sepsis) maintained significantly better cardiovascular performance as evidenced by arterial blood pressure and cardiac output when treated with the RAD as compared to a sham device. These animals also had significantly higher levels of IL-10 — an anti-inflammatory cytokine — and eventually survived longer than their sham-treated counterparts. These experiments paved the way for the first FDA-approved human clinical trial using the RAD bioartificial kidney in intensive care unit patients with acute kidney failure. Human renal proximal tubule epithelial cells were obtained from donated kidneys that were discarded. A total of 10 critically ill patients were enrolled in this trial. The RAD demonstrated device integrity, cell viability, metabolic functionality, and importantly, an immunomodulatory role in these patients with sepsis and multiorgan failure. A follow-up Phase IIb study was unfortunately terminated prematurely because of the lack of a reliable cell source and appropriate technologies to store and use these the RAD units at point of care facilities.
Implantable Bioartificial Kidney
Yeah, the WAK and AWAK are probably more ready for prime time than implanting a bioartificial kidney, but the latter is slated to make a bigger impact once it hits the court. By utilizing a nanofilter and cultured kidney tubule cells to actually mimic a human nephron, this team is taking its time to finish school before declaring its intentions to go pro.
The Bioartificial renal epithelial cell system (BRECS) is a cryopreserved cell therapy system designed to overcome challenges associated with preserving cell culture until its point-of-care use. The BRECS consists of renal epithelial progenitor cells expanded in a perfusion bioreactor and maintained in high density on porous disks. These cells retain their viability and metabolic functions even if reconstituted 3 months later. This device was tested in a porcine model of E. coli induced septic shock and showed prolonged survival of the BREC cohort through stabilization of cardiac output and vascular leak, comparable to the RAD.
Harnessing the strengths of the BRECS, Humes et al developed the wearable bioartificial kidney (WeBAK) for PD. This device uses the sorbent technology to regenerate peritoneal dialysate and the BRECS to provide renal tubular metabolic, homeostatic, endocrinological, and immunologic functions. The WeBAK was tested in an anephric sheep model for up to 7 days of continuous use. The cell viability and metabolic activity of renal tubular epithelial cells was sustained with the regenerated peritoneal dialysate and interestingly, the cell-treated sheep retained neutrophil oxidative activity better than sham-treated sheep, thereby showing a systemic immunological effect. The use of PD as a modality bypasses the limitations of maintaining an anticoagulated extracorporeal circuit with HD. There is no news to date regarding this device’s use in humans.
Physician scientists from Vanderbilt and University of California San Francisco further miniaturized these devices to create the first truly implantable bioartificial kidney, which utilizes the patient’s own heart as a pump, obviating the need for an electrical pump. This device incorporates silicon nanotechnology and cultured kidney tubule epithelial cells to mimic human nephrons. The first part of this device, the high-efficiency filter (HemoCartridge), contains silicon nanopore membranes (SNM) with uniform, elongated, slit-shaped pores, reminiscent of the glomerular slit diaphragms. These are highly selective, therefore retaining larger molecules like albumin, and have low resistance, allowing the patient’s own blood pressure to act as driving pressure. The second part is a bioreactor (BioCartridge) of human proximal renal tubular epithelial cells (PTEC) plated on SNM, which allow for apicobasal transport of the filtrate. The BioCartridge processes the ultrafiltrate from the HemoCartridge and returns salt, water, and glucose to the blood, and concentrates toxins into a small volume of “urine.” The SNM also provides immunoprotection to the PTEC layer. When implanted in six dogs, these devices remained patent and thrombus-free on aspirin alone. Human trials of this device are in the planning stage.
The unique characteristics of this technology compared to WAK/AWAK includes the ability to purify blood without dialysate and to produce a concentrate full of waste products — similar to urine — for excretion. The silicon scaffold between the tubule cells and the patient’s immune system obviates the need for immunosuppressive medications. Although it might be a proverbial “year away” from contending for the championship, this team should not be underestimated on the court!
Scaffolded Bioartificial Kidney
Why make a human nephron when you can grow one? Oh, right, we forgot that the kidney is derived from 26 different cell types, and is more than just a filter. Can we “print” this complex organ using decellularization, scaffolding, and cellular signaling to get everything in its right place? Is this team the real deal or just a pipe dream?
Regardless of the degree of biocompatibility, biomaterials are still foreign to the human body and inherently carry risks of immune system activation. Moreover, bioartificial kidneys can mimic the function of an actual human kidney but likely can never replace it. Therefore, kidney transplantation remains the gold standard treatment for patients with end-stage kidney disease. Given the wide gap between supply and demand of organs for transplantation, scientists have long desired a fabricated bioartificial kidney (or, as modern medicine calls it, a “3D-bioprinted kidney”). The complex structure of the kidney is derived from 26 different cell types in the ureteric bud and metanephrogenic mesenchyme. Intrinsic regeneration has been observed in the kidney proximal tubules after injury, by the proliferation and re-integration of tubular cells. But to replace the function of the native kidney, epithelial, endothelial, and mesangial cells are all required. These cell types should not only be available in enough numbers but should also be able to mimic the autocrine and paracrine functions in order to functionally mimic the natural cell signaling and biofeedback pathways. The scaffold itself should be able to withstand blood flow while maintaining its filtration capabilities, be durable enough to be handled surgically during implantation, maintain in vivo integrity, and be able to perform secretory and absorptive functions and control hemodynamic, endocrine, and immunologic functions.
Current technology is limited in “printing” a complex, multiscale hierarchical organ such as the kidney. For the time being, some researchers are looking at decellularized kidneys as a promising alternative. Decellularization involves removing all cellular material (and immunogens) while preserving the native structure, including matrix architecture and inherent biological clues such as glycosaminoglycans (GAGs), collagen I and IV, laminin, and fibronectin, to stimulate proliferation after reseeding of the scaffold. GAGs bind growth factors like fibroblast growth factor (FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL8) which are important for guiding the differentiation of seeded cells. Potential sources of kidneys for decellularization include human kidneys rejected for transplant, post-mortem donations, or even animal sources like pig, goat, and monkey. Porcine matrices have been shown to promote adhesion, survival, and maintenance of human cells. Once decellularized, these scaffolds can be reseeded with a progenitor population which may include induced pluripotent stem cells (iPSCs), embryonic stem cells, bone marrow derived mesenchymal stem cells etc. Unsurprisingly, both decellularization and reseeding can cause microstructural disturbances in the matrix and/or protein makeup of the scaffold, hence negatively affecting the biomechanical properties as well as the phenotype of repopulated cells.
Numerous challenges remain before a 3D-printed kidney is available for clinical use. Importantly, an ethical and abundant source of human kidney cells needs to be identified, high-speed bioprinting with nanoscale resolution needs to be mastered, and finally, the bio-printed kidney will need to undergo rigorous physiological maturation and functional testing prior to implantation. The question for us is whether this endeavor is a pipe dream, or if we should pin our hopes on the possibility of unlimited organs like this for future transplantation.
Interest in the future of these technologies has been brewing for years, and predicting when they will be available for clinical use remains challenging due to the technical, regulatory, and financial obstacles. It is now 60+ years since Willem Kolff’s first dialyzer; with so many intriguing prospects in the development pipeline, this team has the potential to evolve into a dynasty in the next few years.
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