Innovation pillars can help guide development of dialysis transformation
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Early pioneers including Willem Kolff, MD, PhD, and Belding Scribner, MD, ushered in an era of hemodialysis treatment for irreversible kidney failure.
Imaginative and innovative efforts overcame many developmental challenges and obstacles, and perseverance and achievements were recognized with receipt of the Lasker Clinical Medical Research Awardin 2002 for “the development of renal hemodialysis, which changed kidney failure from a fatal to a treatable disease, prolonging the useful lives of millions of patients.”
Yet there is an increasing view that the status quo of dialysis care is not only suboptimal, but unacceptable. Dialysis today takes an enormous toll on patients, families and caregivers, impacting the ability of patients to live full and productive lives. Problems include the incomplete replacement of kidney function, the intermittent nature of the treatment schedule, ongoing restrictions on fluid intake and dietary choices, and highly restricted mobility during treatment, including ability to travel freely. Twenty years later, we are at the beginning of a new era in which the urgent need is to innovate and develop new treatment modalities that are patient-centered, cost-effective, accessible and offer improved patient outcomes.
In this editorial, we describe five pillars supporting disruptive transformation in dialysis and other therapies for kidney failure.
Pillar 1: Patient activism
Historically, the preferences, priorities, feedback, opinions and feelingsof kidney patients were given short shrift. The Standardized Outcomes in Nephrology (SONG) initiative highlighted the discordance between patient priorities (eg, quality of life) and those of nephrologists. Insights from SONG and other efforts, like the Kidney Health Initiative (KHI) and Innovations in Dialysis Expediting Advances Symposium have demonstrated the value of championing the patient voice in a setting that includes innovators, regulators and health professionals.
Pillar 2: Top-down drivers of change
For many years, especially in the United States, disruptive innovation was hindered by the existence of an oligopoly (two companies controlling most of the dialysis treatment market) and a monopsony (a single-party payer) neither of which were incentivized to invest heavily in new technology. Products such as ultrafiltration control, hollow fiber dialyzers, synthetic dialysis membranes and bicarbonate-based dialysate solutions were beneficial, but overall incremental in improving patient outcomes.
Yet today there are multiple simultaneous top-down initiatives supporting change to transform dialysis. In 2019, KHI published Technology Roadmap for Innovative Approaches to Renal Replacement Therapy. The roadmap has become widely accepted as a technical guidepost for innovative mechanical, cell-based and hybrid new technologies, covering regulatory issues related to risk tolerances, recommendations for clinical trials endpoints and marketing considerations.
Hand in hand with the development of the roadmap, The American Society of Nephrology partnered with HHS to create a Kidney Innovation Accelerator (KidneyX) to support fundamental redesign of dialysis through a series of Artificial Kidney Prize competitions. Patient organizations, such as the National Kidney Foundation and the American Association of Kidney Patients have each taken active steps to financially support dialysis innovators, and to influence governmental and other agencies to support patient-centered innovations.
In Europe, the European Kidney Health Alliance is similarly active in incentivizing change at the policy, regulatory, reimbursement and organizational levels. Globally, the International Society of Nephrology in collaboration with the George Institute for Global Health and the Asian Pacific Society of Nephrology awarded an Affordable Dialysis Prize to design a dialysis system that would run on solar power, cost less than $1,000 and provide treatment for less than $5 a day.
Pillar 3: Emergence of bottom-up innovators
All currently available home hemodialysis devices have fundamental size and mobility limitations that represent barriers to significant expansion in their use. Smaller and lighter machines are required. A major challenge to mobility is the amount of dialysate required to diffusely eliminate enough urea and other toxins.
After a relative lull in activity, the past 5 years have seen an unprecedented expansion in interest and funding for innovation in portable and wearable dialysis technologies from researchers, government agencies and professional organizations. Many of these efforts are being led by “bottom-up innovators” who frequently start as academic investigators and then start small companies. While there are many obstacles that historically hindered the development of truly light and small dialysis devices, the primary technological impediment has been a lack of effective strategies to enable toxin removal without using substantial volumes of dialysate. Multiple teams of investigators around the globe are now attacking this problem using diverse strategies, including the use of sorbents to physically bind toxins, or deploying either electro-oxidation or photo-oxidation technologies to directly degrade urea and toxins in the dialysate.
Finally, substantial efforts have gone into developing implantable bioartificial kidneys and xenografts. Early work from H. David Humes, MD, and colleagues proposed that combining a synthetic hemofiltration device with a bioreactor module containing animal-derived (and later human) renal tubular epithelial cells in an extracorporeal circuit could recapitulate not only the filtration function of the human kidney but also perform resorptive functions otherwise not possible to recreate with conventional diffusive dialysis technologies.
More recently, Shuvo Roy, MD, and William H. Fissell, MD, have also proposed connecting a “glomerulus” module with a “tubular” module for ultrafiltrate reabsorption, based on cultured kidney epithelial cells on silicon membranes. This prevents the need for mechanical pumps or electrical power.
Xenografts hold enormous promise for a potentially unlimited source of lifesaving organs and may ultimately prevent the need for long-term dialysis therapy. Recent technical advances in xenotransplantation surgical technique, immunosuppressive therapies and understanding in systemic responses to xenografts have shown proof of concept and may lead to potential clinical use in the medium-term.
Pillar 4: Precision medicine to dialysis
In 2015, Francis Collins, MD, PhD, and Harold Varmus, MD, announced a new initiative on precision medicine whereby the focus of disease prevention and treatment care strategies would take individual variability into account. The mantra for precision medicine is “the right treatment for the right patient at the right time.” Arguably, in-center dialysis is one of the least precise treatments delivered for a serious end-organ disease, as the dialysis prescription is largely the same whether the patient is aged 20 or 80 years old, has substantial residual kidney function or not, has substantial cardiovascular disease or not, etc. A next generation of dialysis devices can inform and enable the implementation of precision dialysis, whereby patient management is monitored via sensors and tailored to the individual metabolic needs.
Even today, for patients with residual kidney function, upcoming planned clinical trials will test the idea that fewer weekly sessions may be safe and improve overall quality of life and well-being. It will free up more dialysis chairs for other patients to begin dialysis treatments. Finally, it is now increasingly recognized that many uremic toxins, such as indoxyl sulfate and para-cresol sulfate, are byproducts of gut microbial metabolism and once absorbed into the bloodstream, are toxic to the vasculature. Blood concentrations of these toxins, which are protein bound in the circulation and poorly removed by dialytic diffusive clearance, have repeatedly been related to cardiovascular and neurological symptoms, morbidity and mortality in patients.
Ideally, emerging gut-based therapeutics can synergize with extracorporeal strategies to delay the need for initiating dialysis in some cases, help to relieve uremic symptoms and non-invasively enhance dialysis efficacy.
Pillar 5: Overcoming the valley of death
For a new medical device, the road from concept through bench and animal-model testing, human trials and successful product launch is often long and difficult. While there are many developmental stages in which a good concept can fail, it is well recognized that there is a distinct “valley of death” that must be overcome, often between the advanced development stage (which may be accomplished with modest financial resources) and the more resource-intensive commercialization stages.
Conclusion
There is hope today that innovation can provide different kinds of treatments for patients on dialysis that will favorably change results. We must be collaborators in supporting patient-centered innovation to improve current-day dialysis options.
There is also a phenomenon, often referred to as the “hope-hype cycle,” when initial excitement fades into disillusionment because innovation takes longer than expected or desired. As a community, we must stay the course, manage expectations and finally make radically improved treatment options available for patients.
- For more information:
- Jonathan Himmelfarb, MD, is professor of medicine and adjunct professor of bioengineering in the division of nephrology at the University of Washington School of Medicine and was the founding director (2008-2022) of the Kidney Research Institute. He is co-director of the Center for Dialysis Innovation. He can be reached at jhimmelfarb@nephrology.washington.edu.
- Glenda V. Roberts is director of external relations and patient engagement at the University of Washington Center for Dialysis Innovation and Kidney Research Institute. She can be reached at glendar@uw.edu.
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