Artificial Organ Experts Talk About The Development Status, Challenges And Opportunities Of Artificial Kidney
Jun 13, 2023
Currently, renal failure has become a major public health problem worldwide. According to 2021 data, about 4.7 million patients are receiving renal replacement therapy. Due to the lack of kidney resources and other factors, most patients with renal failure receive renal replacement therapy with hemodialysis and peritoneal dialysis, but both dialysis modes have their disadvantages. Hemodialysis has a poor quality of life and a relatively high mortality rate. The quality of life of peritoneal dialysis is high, and the mortality rate is relatively low, but the cost is high, and after a few years, peritoneal dialysis patients may have to switch to hemodialysis due to factors such as technical failure. Given the above reasons, people always hope to develop an artificial kidney system, which can free patients from the shortcomings of traditional dialysis, and increase the autonomy of patients so that they can enjoy normal life and work rights.
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On June 5, 2023, Nature Reviews Nephrology published a review written by experts from the European Artificial Kidney Development Team and Artificial Organ Development Team. After reviewing the current prototypes of artificial kidneys, experts divided artificial kidneys into two categories, wearable dialysis machines, and bioartificial kidneys. These two types of artificial kidneys have their advantages and disadvantages, and opportunities and challenges coexist. In addition, the new semi-permeable membrane technology will help the development of artificial kidneys and even improve the existing hemodialysis technology.
Wearable Dialysis Machine
The pain point of wearable dialysis machines is very significant, namely the regeneration of dialysate. Taking traditional hemodialysis as an example, 4 hours of dialysis requires 120-150L of dialysate. Patients can't carry so much dialysate with them. Therefore, a wearable machine must implement a device that continuously regenerates dialysate in a closed-loop system.
Currently, dialysate regeneration devices used in wearable dialysis machines usually include cation exchangers/membranes, such as polystyrene resins. They remove cations such as potassium, sodium, and hydrogen ions. And anions are also removed by various methods, such as zirconium oxide/polystyrene base with immobilized metal ions (such as iron or lanthanum) to convert phosphate to base. The above method can adjust the pH value of the dialysate, thereby restoring the patient's acid-base and ion balance. In the removal of organic solutes, the commonly used method is activated carbon adsorption. Studies have shown that 81% of organic uremic solutes found in dialysate are adsorbed by activated carbon, including protein-bound solutes.
However, activated carbon cannot be used for urea removal because the affinity of activated carbon for urea is quite low (0.1–0.2 mmol/g usually), and the yield of urea is higher than other organic uremic solutes. Therefore, other methods must be used for removals, such as enzymatic hydrolysis, electrochemical decomposition, and adsorption.
1 Enzymatic hydrolysis
Urease hydrolysis is a very effective strategy, 30~50g of active urease can completely remove the urea produced during 4h dialyzes. However, the decomposition of urea produces ammonium, which is more toxic. Zirconium phosphate can bind ammonium, but at the same time, zirconium phosphate can also completely remove calcium, magnesium, and potassium ions in the dialysate, requiring reinfusion. However, this increases the size and weight of the dialysis machine. If a new type of semipermeable membrane can only adsorb ammonium, the enzymatic hydrolysis method can be widely used.
2 Electrochemical decomposition
Theoretically, electrochemical decomposition could allow the direct conversion of urea to nitrogen and carbon dioxide. These two substances are not toxic and can be discharged directly into the atmosphere. However, the electrochemical decomposition method can also convert chloride ions in the blood to form hypochlorite, and further oxidation may form nitrite, nitrate, ammonium, etc. In addition, the voltage and power required for electrolysis are also pain points for wearable dialysis machines.
Trying other electrode materials seems to improve the aforementioned pain points. Graphite, nickel-copper alloy, and titanium dioxide are all good solutions. Under neutral or slightly alkaline conditions, the above electrodes can oxidize/electrolyze urea, producing less toxic substances. However, whether the above-mentioned electrodes can perform better in complex and variable and used dialysate environments still needs more research.
3 adsorption
Currently, adsorption appears to be the best method for resolving urea in the dialysate. Adsorption can be divided into chemical adsorption (covalent bond) and physical adsorption (dipole interaction formed by hydrogen bonding), in which chemical adsorption is stable, irreversible but slow; physical adsorption is fast but unstable. At present, some alloys and new materials can improve the above pain points. Chitosan is a substance that adsorbs urea by physical adsorption. Although the binding force of chitosan adsorption is low (only 0.2mmol/g), after forming a complex with metal ions, such as copper ions, the binding force can rise to 4.4mmol/g.
In addition, the mixed basement membrane (MMM) composed of polystyrene ninhydrin, polyethersulfone, and polyvinylpyrrolidone also showed a good binding force. The adsorption principle of MMM is chemical adsorption + physical adsorption, with a high rate and stability. It is worth noting that the adsorption capacity of MMM is highest at 70 °C. Therefore, how to make MMM have a higher adsorption capacity at 37°C still needs further study.
bioartificial kidney
A bioartificial kidney (BAK) is an artificial kidney that combines biology and physical chemistry. BAK contains renal proximal cells and has transport, metabolism, and endocrine activities, which can mimic the function of human renal tubules. Unlike wearable dialysis machines, BAK is partially functional by biological methods (cells). Studies on patients with acute kidney injury (AKI) suggest that BAK can improve the survival rate of patients. However, the biggest problem with BAK is the acquisition and storage of cells. If medical institutions or related companies cannot solve the production, transportation, storage, and effective distribution of the above cells, the accessibility of BAK will always be low. In addition, it is also possible to study how to prolong the life of cells to reduce the cost of BAK use.
Remarks: The patient's blood first passes through traditional dialysis equipment to remove albumin, small molecules, and uremic toxins bound to proteins, and then enters the biological reaction equipment. In the bioreaction device, tubular cells reabsorb and transport some of the substances, returning albumin and other useful substances to the body into the blood.
In addition, the challenge of BAK is miniaturization. At present, wearable BAK has achieved initial success in animal models (kidneyless sheep/pigs). In the kidneyless sheep model, no rejection occurred in the sheep, and the successful survival time was more than 7 days. In the pig model, after the implantation of BAK, the pigs did not experience rejection, and the curative effect was ideal.
New Dialysis Membrane
Just like aerospace technology will eventually improve civilian technology. The artificial kidney system designed for extreme conditions (miniaturization, low energy consumption, a small amount of dialysate, etc.) eventually promoted the progress of dialysis membranes and even further optimized the existing hemodialysis technology.
1 polymer film
To increase the lifespan of the dialyzer and reduce the need for patients to replace parts of the dialysis machine. Researchers have been grappling with the biocompatibility of dialysis membranes. Polymer membranes are an effective idea. The polyvinylidene fluoride membrane modified by polyvinyl alcohol and chitosan can effectively improve biocompatibility. Another way of thinking is that adding argatroban or hydrophilic substances to the polysulfone membrane can reduce the risk of thrombosis and increase the safety of hemodialysis.
2-nanometer silicon base film
Traditional silicon-based membranes have poor biocompatibility, short service life, and are prone to thrombus formation. However, with the development of electronic technology, especially photolithography machines, it is no longer difficult to finely manufacture nano-silicon-based films. Nanosilica-based membranes could be the dawn of in vivo hemodialysis devices. In 2022, a nano-silicon-based membrane hemodialyzer was successfully implanted in pigs. This hemodialyzer can perform hemodialysis automatically. Its creatinine and urea clearance rates are equivalent to those of traditional fiber dialyzers, but the blood flow rate is only 1/20. A blood pump is therefore no longer required. Blood flow is achieved by the physiological arterial-venous pressure difference. In addition, this type of hemodialyzer can integrate electronic sensors and micro-motor systems, combined with a 5×5m2 silicon chip, which can generate a multi-parameter medical monitoring system to monitor the situation of hemodialysis in real-time, which is conducive to individualized medical treatment.
3 ion reabsorbed
AWEDI is an ion reabsorbed that combines ion exchange resin, ion exchange membrane, and applied voltage to achieve selective ion reabsorption, effectively mimicking the action of renal tubules. Studies have shown that the AWEDI system can effectively reabsorb sodium, potassium, magnesium, and calcium ions, and even glucose can be reabsorbed. However, the AWEDI system also faces three challenges. First, the AWEDI system has a poor ability to remove uremic toxins with a molecular weight > 180 Da; second, the ion transport efficiency is related to voltage. If the voltage is too high, water may be split to form hydrogen and oxygen; if the voltage is too low, the reabsorption efficiency will not be high; finally, the ion selectivity of different crystals has a large difference (up to 42%), and these differences are related to the size of AWEDI, dialysate concentration, pH value, and even voltage.
Prototype of artificial kidney/wearable dialysis machine
At present, PAKs and WAK are prototypes of artificial kidney/wearable dialysis machines that have been used in clinical research, among which WAK is the most famous. The weight of WAK is about 5kg. Clinical studies have confirmed that WAK can work continuously for 4~8h or even 24h. WAK can provide effective ultrafiltration within 24 hours, and the clearance rates of urea, creatinine, and phosphorus are 17±10, 16±8, and 15±9ml/min, respectively. However, during the 24-h clinical study, excessive carbon dioxide gas in the dialysate and coagulation in the extracorporeal circuit resulted in the early termination of the study.
If hemodialysis is not considered, automatic WAK (AWAK) is a smaller (2kg) peritoneal dialysis device, which can significantly reduce the consumption of dialysate, and most adult patients can carry it with them. A study in 2022 showed that in 14 patients with peritoneal dialysis, AWAK could work 10.5 hours a day for 3 consecutive days. The study showed that AWAK significantly cleared urea (20.8 to 14.9mm; P = 0.001), creatinine (976 to 668uM; P = 0.001), and phosphorus (1.7 to 1.5mM; P = 0.03), and weekly peritoneal Urea clearance index, Kt/V>1.7. No serious adverse events occurred in the patients. Although some patients experienced abdominal discomfort, they were relieved after drainage of dialysate or defecation.
Another 4 PAK prototypes have been released and related clinical research is underway. However, the weight of these PAK prototypes is ≥10kg. Therefore, in terms of portability, it is similar to WAK.
In general, the prototypes of artificial kidneys and BAK have come out one after another. Although there are many challenges, with the progress of medicine and other disciplines, these challenges will be solved one after another. In addition, artificial organs can be added to micro-sensing systems (such as monitoring fluid load, and specific blood components), and combined with technologies such as AI to form individualized medical advice.
References:
1. Ramada DL, de Vries J, Vollenbroek J, et al. Portable, wearable, and implantable artificial kidney systems: needs, opportunities, and challenges. Nat Rev Nephrol. 2023 Jun 5:1–10.
