Chronology

1902 to late 1990s

Clinical and scientific advances helped kidney patients.

First patient treated by dialysis in 1945.

Dialysis shunt developed in 1960.

Medicare authorized ESRD coverage in 1972.

Late 1990s Rapid progress in silicon nanotechnology, membrane filtration, and tissue engineering provided the base of new knowledge required for research on a bioartificial kidney to accelerate.
1998–2010

The Kidney Project launched.

Phase 1 of The Kidney Project completed in 2010.

2014–2017 Phase 2 of The Kidney Project is under way.
2018 Phase 3 of The Kidney Project begins.

History of ESRD treatment: Chronology of scientific developments

Possibility of kidney transplants is explored

1902 An Austrian medical team performs the first successful experimental kidney transplants on animals at the Vienna Medical School
1909 A French medical team performs the first kidney transplant experiments with humans, but with just a two-week survival rate
1933 Russian surgeon Yuri Voronoy performs the first human-to-human kidney transplant in Kiev, Ukraine; like others to follow, the transplant failed due to improper matching

Development of immunosuppressants and blood dialyzers begins

1940’s Sir Peter Medawar experiments with the immunologic basis of organ rejection (England)
1943 Willem Kolff develops the first rotating drum hemodialyzer (Netherlands)
1945 Willem Kolff successfully treats acute renal failure patient with hemodialyzer (United States)
1948 Nils Alwall invents glass arteriovenous shunts, which treats more than 1,500 patients by 1960 (Sweden)
Early 1950’s Immunosuppressant drug use leads to some kidney transplant successes
1954 Joseph Murray and colleagues perform a successful kidney transplant from one twin to another without using immunosuppressive medication (United States)
1960 Belding Scribner and Wayne Quinton develop Teflon® arteriovenous shunts, which revolutionize hemodialysis by eliminating chronic incisions (United States)
1962

Belding Scribner establishes first outpatient dialysis clinic (United States: Seattle, Washington)

Joseph Murray transplants the first cadaveric kidney (United States)

1964/1966 Richard Stewart develops the hollow-fiber dialyzer and Dow Chemical brings the hollow fiber dialyzer cartridges to market; the format is still in use today

Medicare covers ESRD

1972 U.S. Congress passes legislation authorizing the End Stage Renal Disease (ESRD) program under Medicare (United States)

Immunosuppressant drugs become available and
Silicon membranes appear feasible

1983 U.S. Food and Drug Administration approves cyclosporine to prevent organ rejection; drug is still widely used today (United States)
1985 Fresenius Medical care introduces polysulfone membranes for dialyzers; still current material of choice (United States)
1998

Tejal Desai, doctoral student in Bioengineering, reports feasibility of silicon membranes for biomedical applications (United States: University of California, San Francisco and Berkeley)

Collaboration between Dr. Shuvo Roy and Dr. William Fissell begins.

The Kidney Project: Timeline of past work

1998-2010: Phase 1 successes of The Kidney Project research team

During Phase 1 of The Kidney Project, the project’s research team demonstrates the individual feasibility of both components of the bioartificial kidney:

The hemofilter:
  • Fabricate and test robust silicon membranes and confirm satisfactory toxin clearance at pressures comparable to blood.
  • Assess and confirm membrane safety and blood compatibility. Membranes show they do not cause coagulation during short-term laboratory studies.
The cell bioreactor:
  • Establish a reliable supply of human-derived cells and suitable methods of storage.
  • Demonstrate that cells in a miniature bioreactor provide biological activity including the ability to reabsorb water and salts, just like in the healthy kidney.
1998 The Kidney Project begins with a collaboration between Dr. Shuvo Roy and Dr. William Fissell at the Cleveland Clinic, Cleveland, OH
1999 Dr. H. David Humes and his team complete animal testing of the extracorporeal renal assist device (RAD) at the University of Michigan and report feasibility of the device combining hemofiltration and cell therapy for use outside the body
2001 First generation of silicon membranes are constructed
2002 Feasibility of silicon membranes for filtration is tested
2003

Inventors Dr. William Fissell, Dr. H. David Humes, Dr. Aaron Fleischman, and Dr. Shuvo Roy file a patent application with the U.S. Patent and Trademark Office (USPTO) for an implantable bioartificial kidney

Feasibility of cell growth on silicon membranes is checked

2004

The first human trial of the RAD happens

U.S. Patent and Trademark Office issues patent by on implantable bioartificial kidney

Conditions for renal cell growth on silicon membranes are optimized

Size and performance specifications for implantable bioartificial kidney are established

The team develops and launches 10-year research and development plan to achieve first-in-man demonstration

2007

Selectivity of silicon membranes for different solutes during filtration is demonstrated; they confirm endotoxin rejection by silicon membranes and develop analytical model to explain albumin retention by silicon membranes

Performance of biocompatible polyethylene glycol (PEG) coatings applied to silicon is tested; they evaluate blood compatibility of silicon in vivo, prototyped calibrated-shear epithelial cell bioreactor

Membranes are tested to prevent protein fouling and blood coagulation; membranes are designed with > 99% reliability Synthetic glycocalyx for coating membranes is developed

Filtration using both steric and electrostatic hindrances is demonstrated

2009

2nd-generation membranes with high pore density are constructed

Active transport by renal epithelial cells in bioreactor is achieved

Zwitterionic polymers for coating membranes are demonstrated

Theoretical basis for slit pore membrane permeability-selectivity is developed

Protocols for enhanced propagation of primary renal epithelial cells are established

Silicon filter is implanted in small animal surgically

2010

3rd-generation membranes with high hydraulic permeability in situ are constructed; long-term cryopreservation of renal epithelial cells is confirmed

2nd-generation membranes with high pore density are demonstrated

Shear-dependent transport in cell bioreactor is demonstrated, and the team designs artificial kidney device at UCSF

2014-2017: Phase 2 plans of The Kidney Project research team

Phase II began in 2014 with the start of the preclinical studies.  To complete Phase II, the research team will finish the engineering refinements to the device components (hemofilter and bioreactor), complete a rigorous series of preclinical animal studies, and continue to fundraise. Specifically:

Hemofilter and bioreactor components will be refined and tested.
  • The Kidney Project team will finish fine-tuning both the hemofilter and the bioreactor and combine these two components into scaled-up prototypes and test increasingly complex prototypes of the device in stages.
  • The work will involve a combination of engineering improvements to silicon membranes, bench-top experiments with the combined hemofilter and cell bioreactor, and packaging of the device for preclinical testing.
Potential partnerships with industry with be identified and solidified.

After preclinical experiments show successful device performance, The Kidney Project team will implant the bioartificial kidney into patients to evaluate safety and function.

The U.S. Food and Drug Administration (FDA) selected The Kidney Project to a new regulatory approval program called Expedited Access Pathway (EAP). It is intended to bring breakthrough medical device technologies to patients faster and more efficiently.

Goals: Phase 3 plans of The Kidney Project team

We anticipate beginning the First-In-Human testing of the hemofilter device by early 2018, pending no unexpected scientific delays and funding goals are met in a timely manner.

Sources

  1. Roy, S. Briefing: The Kidney Project.
  2. Transplant, surgical
  3. Kidney Transplantation: Past, Present, and Future: History

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