January 24, 2018, for John Hopkins fellowship submission
For over fifty years, dialysis therapy has been the primary mode of treatment for individuals with End-Stage Renal Disease. But precisely due to its success, robust and focused research into renal transplantation has been minimalized over many years.
A. Introduction
Dialysis therapy was soon to be an economic boon to dialysis equipment by ancillary equipment manufacturers. Legally including renal or pancreatic therapies as a catastrophic illness into the Medicare framework in 1972 brought gradual improvements in dialysis technology began to emerge. However, this renewed focus created a renewed reliance on the utilization of kidney transplantation as a primary mode of therapy over dialysis.
B. Complications Related to Hemodialysis
With hemodialysis came problems for a patient, even with its success. An individual receiving hemodialysis has a 20% – 25% mortality rate[1] and a survival rate of 35% after five years of dialysis.
In addition, patients endure travel to clinics and 4 or 5 hours[2] tethering to a dialysis system. This weekly schedule steals time from the normal flow of life. Add this to the hardship and difficulty of maintaining dietary and fluid restrictions for efficient homeostasis. Life-altering traditional dialysis as a treatment modality is challenging to maintain.
Yet, because of its need for repetitive access to the circulatory system coupled with repetitive puncturing. Dialysis needle insertions are repetitive to access the arterialized vein. The procedure eventually dwindles vessels’ accessibility for dialysis, creating the need for repeated surgeries to source new vessels to cannulate.
Traditional dialysis also causes changes in the skeletal, vascular, and organ systems due to its inadequacies within the procedure. Most commonly leading to abnormal bone growth, cardiac, or problems affecting the endocrine system. In addition to the presence of Beta-2-microglobulin. A molecule associated with Alzheimer’s Disease.
The average price tag for hemodialysis therapy is $89,000 per year[3]. The current population of dialysis patients within the United States alone is 650,000. It consumes a total annual cost of $42 billion, and Medicare[4] absorbs $35 billion.
The fundamental concept of hemodialysis can be traced back in history to Dr. Thomas Graham in Glasgow, Scotland[5]. The first use of dialysis to treat an individual with chronic renal failure was done by Georg Haas (Giessen, Germany 1924)[6], followed by Willem Kolff in Kampen, Germany, between 1943 and 1945[7]. He is considered the father of hemodialysis. Yet little in the basic principle has improved over time, and access to an individual’s circulation to propagate the process continues to be a challenge to this day.
For whatever reasons, be they medical, anatomical, physiological, chemical, engineering, or technological improvements. Patients diagnosed with chronic renal failure or Chronic Kidney Disease (CKD get the short straw regarding advanced technologies. New approaches and therapies in dialysis therapy can improve quality of life or long-term outcomes.
A vigorous and more aggressive approach to transplantation research in the new millennium can offer new opportunities for End-Stage Renal Disease therapies. Renal transplantation can be made available to all End-Stage Renal Disease patients as a therapeutic choice.
Then we can relegate dialysis therapy as a supportive or “bridge” role for End-Stage Renal DiseaseStatistics for Renal and Pancreas Transplants
Within the United States alone, 122,325[8] patients are waiting for an organ transplant. Of this number, 78,800[9] individuals are actively waiting for an organ with the correct tissue type and HLA sequence for transplantation. The total number of transplant surgeries performed in the United States between January and August of 2015 was 20,704[10] , and the total number of donors for this same period was 10,051[11]. There is a significant disparity between donated organs and individuals on the transplant list.
D. Renal Transplantation
Out of the number of individuals awaiting transplants presented above, there were 101,189 individuals actively waiting for a kidney transplant[12]. During this period, 17,105 kidney transplant surgeries saw completion[13]. On a daily average[14],
- Add the addition of three thousand (3000) new kidney patients to the transplant waiting list.
- Twelve individuals (12) die each day waiting for a viable kidney transplant.
- In 2014 4,270 individuals died waiting for a viable kidney transplant, and 3,617 became too ill to receive a kidney transplant.
- Of the 17,105 completed kidney transplants mentioned above, 11,570 were from deceased donors, and 5,535 were from living-related donors.
What number of total transplants were pancreas transplants?Pancreas Transplant Statistics
Transplanting a pancreas paints a different picture than for that kidney transplants. Since the first successful pancreas transplant performed at the University of Minnesota in 1968, there have been 5,000 pancreas transplants performed in the United States, with success rates improving steadily[15]. Pancreas transplantation procedures are not as straightforward as kidney procedures. Like liver transplantation, a pancreas can be a whole pancreas or a segment of a pancreas, so long as viable tissue and vasculature are available. Additionally, depending on the situation, a pancreas transplant could be a double organ transplant, kidney, and pancreas, or a segment of pancreas and kidney. In 2008 there were more than 400 pancreas transplants, with more than 800 done in combination with kidney-pancreas transplants[16].
F. Organ Donor Availability – Candidate Screening
There is a wide gap between donors and recipients, and the wait time for a viable kidney is between three and five years[17]. What we’re losing in translation is not so obvious. To harvest the organs of a non-related donor, living or cadaver, the donor must have signed a donor card. There is the requirement of prior authorization to a family member, an individual with power of attorney. There must be mandated consent to harvest organs from any individual wishing to donate an organ, related or non-related to the patient. The individual must undergo a screening process to ensure that they as a donor are healthy and disease-free, improving the outcome of the donor and recipient long term.
1. Live Donor Screening – Related and Unrelated Donation
The screening process for living donors is not simple. A living donor must be free of kidney disease and diseases that could compromise the success of the transplant in the future. An individual donor must be free from diabetes since 30 to 40 percent of people with diabetes have some form of kidney disease in their life.
a) Hypertension
Consider hypertension when an individual is interested in donating a kidney. If elevated blood pressure is well controlled, there is the likelihood that the donation is viable and can function long-term in the recipient.
b) Obesity
Because there is limited research to date on the long-term effect of obesity, there is little information as to the consequences of how it might affect the kidneys. It is recommended for a donor that they maintain consistent body weight, minimize the recommended diet and caloric intake, and exercise.
2. Living Related Donation
Familial donors determined to be a match for the recipient can anticipate surgery. And while yet remote, possible complications related to donating a kidney and possible long-term effects may occur. Sometimes long after surgery. Post-surgical complications related to hypertension may arise after donating a kidney. Or the event of unexpected outcomes may require hemodialysis. After long thought, the patient should anticipate that even family members with good intentions may refuse to donate.
3. Living Unrelated Donation
These individuals must satisfy the exact clearance protocols as those individuals from a family and experience the same concerns of surgery and post-surgical complications as a family member.
4. Cadaver Organ Donation – Screening
(Additional research is needed)
G. The Aging Population of the United States
As the population in the United States matures, an individual’s organs may begin to fail. Within this group, there is a greater need for organ transplants. But outside this group, within the younger population, whether due to disease, genetic makeup, or organ trauma created chemically, mechanically or physiologically, there is also a demand for an organ transplant. So the spectrum of individuals requiring an organ for transplantation is not narrow but broad-based.
H. Cost-Effectiveness of Long-Term Hemodialysis versus Kidney Transplant
So, how does science, which seeks to answer a wide range of questions about the universe, answer the question of increasing the availability of viable organs for individuals for transplant? The “armchair quarterback” approach to organ transplantation research does not seem to provide the answers. Hemodialysis, the most common form of treatment for kidney failure, it’s fundamental concept was discovered in 1854 by Scottish chemist Thomas Graham, was successfully used to treat acute kidney failure by Dr. Willem Kolff during World War II and continued providing success by treating this type of kidney failure during the Korean Conflict. From this point, while undergoing ‘evolutionary’ improvements, hemodialysis fundamentally has not changed in over fifty years. A considerably more focused, concentrated approach must be emphasized toward transplantation research, specifically to the kidney and pancreas. A multifocal approach needs to be established, de novo if necessary, to reduce the time frame by which individuals are actively waiting for an organ transplant.
I am proposing a unique research facility solely created to promote basic scientific research into the use of induced, adult, parthenogenetic. Embryonic pluripotent stem cells into organ transplantation reduce the organ-recipient gap and bring renal and pancreatic transplantation to the forefront to successfully transplant these organs within the next 10 years.
I. Today’s Research in the Areas of Pancreas and Renal Therapy
Type 1 diabetes and End-Stage Renal Disease have experienced a lack of interest because the current therapies stabilize a patient but provide a slight improvement in long-term outcomes. Results are a paucity of research beyond these therapies to improve patient survival and reduce the cost of both therapies. A prime example is hemodialysis.
In 1960 during the Korean Conflict, Dr. Belding Scribner successfully treated chronic renal failure in soldiers with battle wounds caused renal failure. Because both diseases have a methodology of treatment that sustains the patient, scant research in these areas has occurred beyond simply sustaining the patient. There needs to be more vigorous patient-focused basic applied research beyond the current level today, to improve patient outcomes in these treatment methodologies providing patients with a fuller and more enjoyable life beyond sustainability.
J. A Brief Timeline of Kidney Dialysis (Hemodialysis)
1. Discovery of Dialysis
In 1854 Thomas Graham, a Scottish chemist at the University of Glasgow, pioneered experiments in removing a substance from a fluid. And Dr. Richard Bright at the University of Edinburgh described the clinical features of diagnosing renal failure.
Graham fashioned a membrane from an ox bladder, secured it around the open end of a bell-shaped vessel, and then added urine. This instrument was then suspended in a vessel with a large volume of distilled water for several hours after removing the urine from the bell-shaped vessel, revealing distilled water evaporation. A residue remained at the bottom of the vessel, which Graham determined to be sodium chloride and urea, the two main components of urine. With this simple experiment, Graham had proven that simple diffusion had occurred. The molecules of urea and atoms of sodium and chloride had moved across the ox bladder membrane from the urine into the large volume of distilled water. Doctors Graham and Bright hypothesized that it would take about 60 years to successfully develop a functional dialysis system and treat individuals suffering from kidney failure. It took 89 years for a physician to successfully develop a prototype artificial kidney to treat a patient with acute renal failure successfully.
K. Donor Availability
L. The Aging Population of the United States
Although the plan is to focus solely on renal and pancreas transplantation, basic or fundamental research is essential to flesh out the understanding of renal and pancreas transplantation. The Center or Institute would not be without the essential and critical facilities required for disruptive research into renal and pancreas transplantation.
Some of the essential facilities would include but are not limited to,
- Animal care facilities
- Surgical
- Cage
- Sterilization area – for both animal care and laboratory needs
- Intensive care for both large and small animals
- Animal safety
- Common laboratory facilities
- Flow cytometry
- Image analysis
- Isotope image analysis facility
- Genomics and proteomics core facility
- Histology
- Clinical chemistry
- Pathology
- Microbiology
- Basic biological facility
- High throughput facilities?
- Environmental Health and Safety
- Radiation
- Chemical
- Hazardous waste
- Faculty to train staff and implement safety protocols
- Area for depositing radiation, chemical, and biohazardous waste for transport from the facility.
- A local company hires transportation to the aforementioned hazardous items for proper treatment and disposal
- Ancillary support items
- Gas vendor
- Dry ice vendor
- Ice vendor or large community ice machine, or several ice machines, strategically located
- Varying companies enable purchases of laboratory equipment, specialty equipment, and basic supplies.
- Equipment maintenance facility with staff
- Preventative maintenance
- Calibration and maintenance of biosafety cabinets and chemical fume hoods
[1] https://pharm.ucsf.edu/kidney/need/statistics
[2] https://pharm.ucsf.edu/kidney/need/statistics
[3] https://pharm.ucsf.edu/kidney/need/statistics
[4] https://pharm.ucsf.edu/kidney/need/statistics
[5] https://en.wikipedia.org/wiki/Thomas_Graham_%28chemist%29
[6] https://en.wikipedia.org/wiki/Georg_Haas_%28physician%29
[7] https://en.wikipedia.org/wiki/Willem_Johan_Kolff
[8] Organ Procurement and Transplantation Network, as of December 6, 2015.
[9] Organ Procurement and Transplantation Network, as of December 6, 2015.
[10] Organ Procurement and Transplantation Network, as of November 27, 2015.
[11] Organ Procurement and Transplantation Network, as of November 27, 2015.
[12] Organ Procurement and Transplantation Network, as of September 8, 2015.
[13] Organ Procurement and Transplantation Network.
[14] Organ Procurement and Transplantation Network.
[15] National Kidney Foundation.
[16] National Kidney Foundation.
[17]Johns Hopkins University, Comprehensive Transplant Center.
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