“The past is the experience, the present is the experiment, and the future is the expectation. So invest the experience in the experiment to meet the expectations.” - Unknown
The “Experience”
Dr Thomas Graham, a 19th- century chemist whose scientific work on osmotic forces of fluids paved the way to the present form of blood purification techniques and coined the term ―dialysis‖. In 1913, Dr John Jacob Abel, an American pharmacologist and biochemist attempted dialysis in vivo. Although his attempts were futile in human trials, his machine was dubbed as the ―artificial kidney‖. In 1945, Dr Willem Johan Kolff, a Dutch scientist, who is recognised as the ―Father of artificial organs‖ was the first to perform the successful hemodialysis (HD) on a patient with acute kidney injury (AKI). He used cellophane as the membrane (connected to the circulation) immersed in a drum pool of dialysate (saline solution) and removed 60 grams of urea over 11.5 hours, and called it the ―rotating drum kidney‖ (1). In 1973, with significant advances in vascular access for dialysis and political reforms to include dialysis under Medicare coverage, maintenance HD became a reality for chronic kidney disease (CKD) patients (2). Peritoneal dialysis (PD) remained a treatment for AKI, until Tenckhoff described the use of silicone-rubber-based permanent indwelling catheter in 1976. Over the last five decades, undoubtedly, dialysis has saved millions of lives worldwide, and the field is in a continuous process of evolution (3).
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The United States Renal Data System (USRDS 2016) has estimated an annual cost of over $30 billion for treatment of End-stage renal disease (ESRD), of which the most common treatment modality is HD (87.7%) but fails to restore full health. Although Kidney transplant (2.5%) with overall low cost, more prolonged survival and better quality of life is the best form of renal replacement therapy (RRT) at present, the procedure is limited by non-availability of donors worldwide, and the remaining patients are maintained on PD (9.6% ).
Most of the CKD patients are treated with in-centre intermittent HD (conventional HD), which is given three times a week, each session lasting for 4 hours, resulting in excess water removal and less solute removal. Moreover, the time and cost spent on travelling to the dialysis centre, the need for workforce, electricity and disposables (120-140 litres of dialysate per session) are significant drawbacks. Also, these patients have to be on dietary restrictions, and limitation of movements during HD sessions significantly impairs the quality of life. Although PD provides a form of RRT outside a hospital setting, the level of blood purification is relatively low and overtime, the functionality of peritoneal membrane decreases due to toxic effects of high glucose concentration in PD solutions and recurrent infections of the peritoneal membrane. In North America, the reported mortality rate is 5% to 10% for patients in the waiting list for renal transplants, and within ten years around 40% of patients lose their graft function or die post-renal transplant with average long term graft longevity of 12 years (4).
The most common form of RRT at present is conventional HD that relies on solute removal for blood purification by diffusion, convection and adsorption, either used in isolation or in combination (5). PD uses diffusion and convective methodology to transport and regulate solute movements. A high concentration of glucose is required in the PD fluid to
facilitate ultrafiltration. The solutes can be divided according to their molecular weight (MW) into low (15000Da). Traditionally, the effective clearance of urea by hemodialysis is based on the KT/V model (K = Urea clearance, T = per unit time and V= total body water). Sufficient clearance is achieved when weekly KT/V is ≥ 1.2 for conventional HD and ≥ 2 for PD. The middle molecules (β2-microglobulin, parathyroid hormones) and large MW protein-bound toxins are not efficiently cleared by conventional HD. Serum β2-microglobulin level is often used as a surrogate marker of these middle molecule clearance in HD setting. Most studies have shown ineffective removal of middle and large MW toxins leading to dialysis-related amyloidosis, and increased prevalence of cardiovascular diseases in CKD patients (6).
Many studies have proven that daily extended dialysis provides better quality of life, improved blood pressure control, reduction to no use of phosphate binders, improved bone mineral metabolism and enhanced clearance of middle molecules. The slower solute and fluid removal prevents frequent episodes of intradialytic hypotension, leading to regressed myocardial stunning (7).
All the factors mentioned above demand a change in the current clinical practice to achieve a better clinical outcome in CKD patients by prolonging the longevity, improving the quality of life and decreasing the number of the donor to recipient ratio mismatch. Developments in the field of nanotechnology, sorbent systems and cell culture techniques show a promise to achieve these goals.
The “Experiment”
The ideal alternative therapy for CKD patients should constitute ―3Cs‖ and ―3Rs‖, viz Cost-effectiveness, Convenience (better quality of life) and provide Clearance and at the same time be Reliable (easy monitoring), have Reduction in size, expense and number of disposables, and aid Relocation of patients to home from a health care facility. Among the many concept models on the field of artificial kidneys, only a few innovations are in advanced stages of research. The four main devices that are in the verge of breakthrough that meet the above criteria are the wearable artificial kidney (WAK), automated wearable artificial kidneys (AWAK), implantable artificial kidney (IAK) and the renal assist device (RAD).
WAK:
The WAK is a blood-based renal replacement system that weighs < 5kg with a battery-operated belt type model. This system uses regenerated dialysate using advanced sorbent technology. The system is connected to a double lumen HD catheter using 0.45% sodium chloride solution as a primer. The blood is initially anticoagulated through a heparin syringe pump. The anticoagulated blood and dialysate propel into a polysulfone- based hollow fibre dialyser. The pulsating blood pump uses a pull and push pattern, alternating such that the dialysate compartment is at the peak flow when the blood flow is at trough, and vice versa resulting in effective clearance of solutes. The purified blood then goes through a gas bubble detector chamber before being returned to the patient. The ultrafiltrate is controlled by a pump mechanism which diverts a portion of regenerated dialysate into a waste bag. It has a safety mechanism to stop ultrafiltration if the blood flow is halted (8).
WAK and AWAK use advanced sorbent technology, which is the first or second generation REcirculation DialYsis (REDY) sorbent system which contains several layers.
The spent dialysate is passed into a chamber containing activated charcoal for removal of non-urea organic compounds. The next column contains enzyme urease which hydrolysis urea into ammonia and carbon dioxide. On hydration with water molecules, hydrogen ions from the water molecule convert ammonia into ammonium and carbon dioxide is converted to bicarbonate and hydroxide. Subsequently, the zirconium phosphate ion layer, exchanges hydrogen or sodium ions for the spent dialysate containing potassium, magnesium and calcium. Similarly, the ammonium produced is bound by negative charge and removed from the spent dialysate. Finally, zirconium carbonate and zirconium oxide adsorb phosphate and releases bicarbonate, hydroxide and acetate (9).
In 2007, Davenport et al. conducted the first pilot study on eight patients using WAK over 4 to 8 hours which showed promising safety and efficacy of WAK model (10). Following this, Gura et al. conducted a Food and Drug Administration (FDA) approved human trial of WAK on seven patients over 24 hours and reported a mean clearance of the middle molecule β2-microglobulin (5±4ml/min), phosphate (15±9 ml/min), urea (17±10ml/min), creatinine (16±8 ml/min) and 24-hour ultrafiltration (1002±280 ml). Though the initial trial included ten patients, the trial was stopped after the seventh patient due to technical problems of excess gas bubble formation, kinking of the tube and variable pump function. Five out of the seven patients completed the study (one subject had clotting of blood circuit following ambulation, and the others were discontinued owing to pinkish discolouration of dialysate, suspicious of hemolysis). The data suggests an adequate clearance of middle molecule, maintenance of electrolyte and fluid balance, and better quality of life (11).
The WAK has its advantage of being light-weighted, requiring around 400mL of dialysate, ergonomic to be worn as a belt, no dietary restriction, allowing the patient to ambulate and better quality of life with improved solute clearance and decreased side effects. The inclusion of biofeedback controller system in WAK to monitor blood, biochemical and thermal changes help in achieving the target treatment dose and avoids any hazardous intradialytic events (12).
The disadvantages of WAK include the technical challenge of vascular access as current vascular options have a high risk of bleeding with the use of anticoagulants and are prone to accidental disconnections (13). The long term vascular catheters are advocated rather than needles to prevent dislodgement. However, the risk of long term indwelling
vascular catheter-related infections and consequences of continuous use is not well defined. Secondly, if premature saturation of zirconium phosphate ion-exchange channel occurs, the ammonium may breakthrough into the dialysate and thus into the patient causing more toxic effects. The breakdown of urea releases carbon dioxide gas, which may inadvertently pressurise the space of dialysate, causing mechanical system failure and reduced ultrafiltration (14).
AWAK:
AWAK, also known as WAK-PD, is a tidal peritoneal dialysis based artificial kidney model currently under human trials. AWAK regenerates dialysate to minimise fluid requirements. The AWAK consists of a miniaturised disposable module (storage and enrichment compartment, sorbent cartridge and tubing set for ultrafiltrate) which is encased in a durable module containing the batteries and controller pumps. Similar to conventional PD, a reserve volume of 1.5 litres of dialysate is instilled into the peritoneal cavity which absorbs waste products, toxins and fluid through the peritoneal membrane. In the WAK-PD, an equilibrated dialysate tidal volume of 500mL is drained from the patient and passed through the storage system and pumped through the sorbents for removal of toxins. The dialysate is then filtered and supplemented with a prescribed amount of glucose and returned to the peritoneal cavity. Each tidal exchange takes about 7.5 minutes, providing an average flow of 96 litres of regenerated dialysate per day. The reserve volume of dialysate is circulated back into the peritoneal cavity, and the ultrafiltrate is drained into a collection bag which is discarded along with the disposable module every 7 hours.
The advantages of AWAK include bloodless, easily portable miniaturised device weighing < 2kg, which can be worn like a purse. The dialysate requirement is only 2 L/day compared to 12 L/day in conventional PD, leading to a decreased risk of herniation, abdominal pain and distension. The weekly clearance of urea estimated by KT/V model using AWAK was much above than that of conventional PD. A study using AWAK for 4 to 24 hours in 20 male patients showed an average urea clearance of 31.4mL/min and improved phosphate and middle molecule clearance which is better than conventional PD (15).
Similar to WAK, gas bubble formation leading to mechanical failure is seen in AWAK, and this issue is being addressed in the second generation modules by the inclusion of a degassing unit similar to the ones used in WAK systems. The sorbent cartridge (disposable module) has to be replaced every 7 hours requiring storage of multiple sorbent cartridges in both AWAK and WAK models. The risk of peritoneal sclerosis, hyperglycaemia and membrane failure following a regenerated dialysate is not well known at this time.
The Vicenza Wearable artificial kidney (ViWAK):
ViWAK is similar to AWAK with an additional concept of a computer-based handheld remote. However, the device has not reached clinical trials and requires an addition of an injection system to infuse glucose and bicarbonate (16).
IAK:
The IAK currently under preclinical study weighs less than 500g, incorporates tissue engineering and silicon nanotechnology into a device which can mimic a native kidney following surgical implantation. The device consists of a HemoCartridge (high flux and high selective filter) with a BioCartridge (bioreactor of culture renal tubular cells). Following implantation similar to renal transplant, the ultrafiltrate from the HemoCartridge is processed by the BioCartridge which returns essential water, glucose and salt back into the blood and concentrates a small volume of toxic fluid similar to urine which is drained into the bladder.
The device functions with patients own blood pressure alleviating the need for blood pumps and non-requirement of dialysate. The blood conduits are engineered to prevent stagnation of blood and shear stress avoiding the need for anticoagulation in animal models, and no immunosuppressant drugs are needed as the BioCartridge scaffolds serve as a barrier preventing cellular and molecular effectors from interacting with tubule cells. Thus, avoiding the activation of patient’s acquired and innate immunity.
The disadvantages include frequent monitoring of electrolytes and hydration to replenish the extracellular fluid volume and restriction of diet. No data is available regarding the longevity of the device and the need for additional surgeries to replace the equipment. The ―culture stress‖ where the mammalian cells undergo erosion of fundamental phenotypic properties was seen in the animal models (17).
Stem cell therapy and Bioartificial kidneys:
Stem cell therapy uses the glomerular microarchitecture, and vascular mechanical properties of extracellular matrix (ECM) from discarded human kidneys to provide a decellularized kidney scaffold using various solution strategies. These scaffolds may later be used for cellular regeneration using embryonic stem cells (ESCs), human inducible pluripotent stem cells (iPSCs), human amniotic stem cells (HASCs) and human renal cortical tubular epithelial cells (RCTEs) injected either through the intravenous route, subcapsular or cortical injections. Ross et al. have successfully re-cellularized a kidney scaffold using ESC in a mice model which may hold promise for kidney regeneration using natural scaffolds in the future. However, till date, a standardised protocol for decellularization and recellularization technique has not been accepted (18).
The bioartificial hybrid kidney is also known as the Renal assist device (RAD) comprises an active renal tubular cell reactor and a passive hemofilter, which is designed to mimic the secretive and reabsorptive functions of nephron tubule. RAD has completed phase II clinical trials on patients with acute kidney injury (AKI) and multiorgan dysfunction syndrome, which showed excellent safety and absolute risk reduction of 20% and a 40% relative risk reduction in mortality. These results show a tri-fold improvement in the treatment of sepsis compared to other recent pharmacologic trials in AKI setting.
Though RAD requires an extracorporeal circuit with peristaltic pumps to provide the driving force and lacks consistent cell sources for production, it has its advantage of being dialysate-free and offers the metabolic and endocrine function to some extent which other dialysis strategies do not provide (19). In future, cell sourcing issues for RAD may be addressed with the development of Bioartificial Renal Epithelial Cell System (BRECS) which cultures and cryopreserves the renal epithelial cells (20).
The devices mentioned above though under preclinical and clinical research stages have a distinct advantage of being free of wired electricity, least requirement of dialysate, decreasing the stress on the family and generating less waste than conventional HD. These devices show significantly improved clearance than presently available options, better indexes of bone mineral metabolism, reduced incidence of ultrafiltration mediated hypotension and most important of all improving the quality of life.
The cost information is not available for any of these devices at present. However, with an increase in the number of patients preferring these advanced options, the health care burden for treatment of ESRD would be significantly reduced.
THE “Expectation”
The Advancing American Kidney Health (AAKH) initiative was launched in July 2019 with a tri-pronged strategy to reduce the number of CKD patients, to increase the use of home dialysis and increase the number of renal transplants. This initiative also encourages and acknowledges the developments in the field of artificial kidneys. The AAKH through the KidneyX (the Kidney Innovation Accelerator) foundation provides funding for the new technologies of ESRD. Similarly, the FDA’s Center for Devices and Radiologic Health (CDRH) has initiated a competitive program to encourage innovations in the field of ESRD (21).
The Debiotech of Switzerland, Dutch kidney foundation (Neokidney development program) and AWAK technologies of Singapore collaborated in 2017 to develop a portable artificial kidney that would be cost-effective and ergonomic, enabling frequent and more prolonged home dialysis (22).
In conclusion, a combination of new technology integrated with continuous follow- up involving a multidisciplinary team of clinical researchers, engineers, social scientists and economists is required to realise the dream of revolutionising the treatment of CKD.
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