Plans to develop an implantable artificial kidney have been waylaid by fundraising challenges and the COVID-19 pandemic, but researchers hope to soon have a business case to move the work forward in clinical trials, the project’s co-director said during Kidney Week 2020 Reimagined.
“This is envisioned to be a device that provides the key functions of a kidney transplant,” said Shuvo Roy, PhD, technical director of The Kidney Project, an effort housed at the University of California, San Francisco, and Vanderbilt University Medical Center, to develop an implantable device to provide kidney replacement therapy.
Designed to be inserted in the abdomen, the device will combine two features: a mechanical ultrafiltration unit called a hemofilter, which can remove toxins from the blood by passing it through silicon membranes fabricated with nanometer-scale pores; and a bioreactor, which will contain cultured human kidney cells to perform kidney functions such as maintaining adequate fluid volume and producing hormones. It will not require electrical power, instead operating off the body’s blood pressure. Unlike a transplant, no immunosuppression will be necessary.
According to Roy, the basis for a bioartificial kidney can be traced back to pioneering work conducted at the University of Michigan in the 1990s and early 2000s by nephrologist H. David Humes, MD. Humes used one dialyzer for clearance in his model and a second dialyzer lined with kidney cells. A bioreactor connected to a hemofilter is similar to how the tubule is connected to the glomerulus in the natural kidney. Preclinical experiments demonstrated that renal cell therapy through this Renal Assist Device (RAD) could provide physiological treatment for acute kidney injury.
A later clinical trial (1) in acute kidney injury patients demonstrated that survival among patients treated by RAD was 50% better than among those receiving standard continuous renal replacement therapy. The improvement in survival could be attributed to kidney cells in the bioreactor, Roy said.
“The work was notable in that it was the first-ever demonstration of cell therapy to treat kidney failure in patients,” he said, but it was a large, complex system with at least two dialysis machines, lots of tubing and multiple pumps. Roy partnered with nephrologist William H. Fissell, MD, now at Vanderbilt, and set out to make a smaller, implantable version of the RAD system.
The team took an engineering approach to designing a miniaturized system, Roy explained. Although in cardiology, engineering helped the cardioverter defibrillator go from “a bulky bedside machine” to an implantable device, the fundamental workhorse of dialysis machines—the hollow fiber membrane dialyzer—“has not changed much since being introduced over 50 years ago,” he said. “While there have been some material improvements, it still requires high-driving pressure to drive blood through them, they do not remove toxins efficiently…and they clot and stop functioning after some time of use.”
The Kidney Project investigators used semiconductor silicon wafers to build a new nanopore membrane engineered to be thin and robust, Roy said: “They are precisely machined with pores that mimic the natural kidney’s microstructure.” The team can modify the surface of the membranes by adding thin-film polymer chemistries to prevent fouling and reduce the likelihood of clots. They also can add to the surface different extracellular matrix materials that provide a more physiologic environment to support the growth of kidney cells.
Investigators have tested the prototype hemofilters and bioreactors in pigs. The hemofilter design has been refined such that blood flow is successfully maintained through the device for as long as 30 days using only antiplatelet therapy, not systemic anticoagulation, Roy said. Additional studies have shown the hemofilter can provide urea and creatinine clearance after implantation in pigs for at least three consecutive days without blood thinners.
The initial bioreactor prototype, about the size of a deck of cards, contains human kidney cells behind precisely sized pores that prevent the transport of immunogenic components and provide immunoprotection, he said. The team has tested the device implanted in the neck of pigs, with no immunosuppression or systemic anticoagulation used. After three days, investigators removed the device and studied the kidney cells for signs of rejection. The human kidney cells remained in place within the bioreactor and remained healthy despite being exposed to a foreign immune system, with no clots. Roy presented some of this work during Kidney Week 2019. Both parts of the system could work just using the body’s own blood pressure without the need for local/battery power or external electrical connections.
“The next steps are to scale this up, integrate the two components and show function in an appropriate model of kidney failure,” he said. “This is not without its risks as an ambitious project.”
Roy said he envisioned the device being about 300–600 mL in size, “akin to a large coffee cup,” with a weight of “hundreds of grams.” The devices should last many years, he said, although in a patient preference survey conducted with the American Association of Kidney Patients, many patients reported they would find a maintenance period of two years acceptable.
For more information, see https://pharm.ucsf.edu/kidney.
Tumlin J, et al. Efficacy and safety of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol 2008; 19:1034–1040. doi: 10.1681/ASN.2007080895