Originally published in Volume 38 Issue 12 of Artificial Organs, 19 December 2014
These reminiscences are dedicated to the real pioneers in peritoneal dialysis (PD) who set the foundations for our subsequent contributions. The list of contributors is vast, but three investigators that cleared the road for further development always come to mind: Georg Ganter— who first used PD clinically 1; Fred S.T. Boen—author of the classic compendium on the physiologic principles of PD and who so generously shared his ideas and memories with me 2; and Henry Tenckhoff—who made multiple contributions to both PD access and devices 3.
Nephrology did not officially exist when I attended medical school; it was only referred to as cardio-renal. What impressed me the most was that for the first time in the history of mankind, we had the ability to substitute a vital organ with artificial means on a chronic basis. As such, “nephrology” was the harbinger of a new approach to medicine. Fortunately for me, our university hospital was incredibly understaffed, so I was able to help with whatever I wanted, including performing manual intermittent peritoneal dialysis (IPD) using repetitive peritoneal punctures for acute renal failure or for the occasional patient awaiting a renal transplant. We also performed chronic hemodialysis (HD) via Scribner shunts for blood access and either Kiil dialyzers or coils using RSP machines. Despite my inclination for all things mechanical, at that time I was not truly interested in dialysis as much as renal physiology. I saw the kidney as a great regulator of vital body processes, such that understanding kidney function would allow investigators to intervene by mechanical, pharmacologic, surgical, or nutritional means. In my eyes, the future nephrologist would become “the doctor’s doctor.” I made up my mind to seek my internship and residency in an institution that would combine basic research and clinical science in their training and that had a strong and well-financed physiology department with an interest in calcium and phosphorus metabolism. I found that place on the plains of Minnesota at the Mayo Clinic.
George Bernard Shaw once said: “If you have an apple and I have an apple and we exchange these apples then you and I will still each have one apple. But if you have an idea and I have an idea and we exchange these ideas, then each of us will have two ideas.” I lived that concept at Mayo, a most generous institution. Their wealth of knowledge, technology, and systems in place was unbelievable. Everyone had a special expertise, shared their ideas with whoever showed interest, and was ready to collaborate on any project. My assigned mentor made it clear that he was there to help me and facilitate any opportunities that I identified to enhance my stay at Mayo. He lived up to those expectations. My first request was to have a straight medical internship with emphasis in endocrinology, cardiovascular and renal. During my second year of residency, I requested time in the Physiology and Biochemistry research laboratory under the direction of Dr. Frank Knox. Frank suggested that I applied for a National Kidney Foundation Postdoctoral Fellowship. Fortunately, I was granted the fellowship and joined a fabulous group of scientists to pursue my advanced degree. The big emphasis was on sodium and bone metabolism. Everyone on the team seemed as interested in my research as in theirs. Their contributions and teachings were invaluable. Every project became a fluid and dynamic process with ever-changing possibilities, opening the doors for other experiments. My life was like a river, always changing.
I continued my clinical training along with basic research, thanks to my mentors Cameron Strong, then the chief of the Renal and Hypertension Section, and James C. Hunt, who became the Chairman of the Mayo Clinic Board. Thanks to these gentlemen, I was exposed to the most interesting and complex cases imaginable, some impressive personalities from the business and political world, and most importantly, to all the visiting luminaries, the most impressive of whom was Belding Scribner. I was assigned to show him around during his visit around 1972. It was difficult to believe than such a warm and unassuming man would harbor so much genius, wisdom, and love for mankind. Later in my career, I had the opportunity to share a week with him during a meeting in Hawaii. From him I learned the real history of dialysis while my wife received a crash course in volcanology, one of “Scrib’s” many interests outside medicine. Although I was never his formal student, I learned much from him and his contributions had great influence on my thinking.
Dr. Hunt became an intellectual father and allowed me to modify my curriculum in any way I wanted as long as I performed all my assigned clinical and research duties. He was a very caring and loyal chief to each of his residents and staff, and inspired so many of us with his contagious energy. My years in Minnesota were full of excitement. I finished my Internal Medicine Residency, passed the first Nephrology Boards, obtained my postgraduate degree, and published various articles in diverse topics such as acute renal failure post contrast media 4, renal biopsies 5, late-onset immune deficiency 6, and renal physiology 7, 8. I was honored to be invited to stay at Mayo, but my insecurity plagued me with the thought that perhaps I was not good enough and all the apparent success was due to the influence of that cathedral of medicine.
Thanks to my network of prominent mentors and friends, I received attractive offers to join other well-known academic institutions. However, as luck would have it, I decided to take a sabbatical break in the mid-1970s and join two nephrologists who had also trained at Mayo in a private practice in Charlotte, NC with a clinical academic appointment at the University of NC. There was very little activity in chronic PD at the time and I was one of the first to offer and perform insertion of Tenckhoff catheters east of the Mississippi. Within a year, our PD and Home HD programs had grown substantially. Our home training facilities exceeded the physical capabilities of our building and we soon created a truly modern facility with dedicated nursing and dietary staff, and a group of surgeons who became integral contributors to our success. A year became a lifetime. I was fortunate to have been able to maintain my academic ties and to also work closely with the industry in developing new therapies and technologies while directing a large clinical group.
Chronic PD in the 1970s consisted mostly of IPD using a large proportioning system, glass bottles of dialysate concentrate, and reverse osmosis (RO)-treated water. In the long term, this approach proved to be highly inadequate after the first 2 or 3 years due to loss of residual renal function 9, 10. In 1978, I attended the First International Meeting of PD in Chapala, Mexico, and was truly impressed with the Moncrieff and Popovich presentation of the continuous ambulatory PD (CAPD) concept, based on equilibration PD 11. Despite its simplicity and portability, in my view, CAPD lacked flexibility of prescription and required multiple procedures during the day in uncontrolled environments, with the potential risk for peritonitis. I did not personally consider this adequate for someone with an active lifestyle. CAPD, as conceptualized, was also particularly inconvenient for children, as it would negatively affect the child’s activities and the lifestyle of their mother or caregiver. These thoughts became my first motivation and inspiration for automating the system using a simple cycler while retaining the advantages of equilibration dialysis.
The second consideration was empirical. For some time, we had been impressed with a large anuric patient treated with IPD for several years who had done remarkably well in terms of nutrition and quality of life. However, he was always exceeding the prescribed volume of concentrate. Upon further investigation and a long conversation with his wife, it became apparent that he was undergoing dialysis almost daily and retaining the last 2 L during the day because an empty peritoneal cavity caused him abdominal pain. Basically, he was on an intensive regimen of continuous cycling PD (CCPD) using enormous dialysate volumes, a very cost-ineffective therapy. From this realization, further development was simply a matter of finding an inexpensive, user-friendly, and reliable cycler to provide CCPD. This was a relatively simple task because the only manufacturer of PD cyclers to my knowledge was a small company in New Jersey, American Medical Products (AMP), who had been manufacturing cyclers based on Norman Laker’s original design 12.
After a single meeting with AMP, it became apparent that they had great interest in producing the necessary equipment using my design and prescription requirements. The first step was to modify their existing equipment to accommodate the CCPD prescription. This was accomplished by replacing the mechanical clocks with electronic ones, thereby allowing longer dwell times, adding servo-controlled occluders to improve the precision of dialysate flow and reduce noise and modifying the tower to make it more stable. By 1980, we had a working model that became the AMP 80/2 cycler, the precursor of a long series of future cyclers based on the gravity infusion and drainage principle. The cycler was subsequently further developed, improved, and manufactured by Delmed, who acquired AMP, and finally Fresenius USA, who acquired Delmed. Since then, many cyclers have been developed by several manufacturers. The most recent devices use active infusion (pumping) and drainage, modern and convenient connectology, sophisticated computerized programs adaptable to all prescriptions and maintenance of electronic records, improved user interface and Internet-based communication systems. These developments have improved patient safety and made the 21st century PD cycler more convenient to use. The next step in this natural evolution will likely include miniaturization of the system to make it highly portable and potentially wearable.
CCPD was the virtual reversal of CAPD; the shorter cycles were now provided automatically while the patient slept, and the long nocturnal cycle of CAPD would occur during the day 13, 14. This provided complete freedom for daily activities without any procedure-related interruptions, as well as a controlled environment to perform connections that could result in a lower rate of peritonitis, the most common complication of CAPD. In addition, the first event after a connection was drainage of spent dialysate or “flush before fill.” If contamination had occurred during the connecting procedure, this flow pattern could reduce contamination and theoretically reduce the rates of peritonitis. Early clinical observations suggested that using the same volume of dialysate and dwell time led to higher clearances of small molecules with CCPD compared with CAPD. This observation was reasonably questioned by some. Eventually, we figured out the physiologic explanation. Fukudome et al. showed that portal blood flow, an indicator of peritoneal blood flow, significantly increased in the supine position 15. Thus, we postulated that the effective peritoneal surface area in contact with solution would increase in the supine position. Because most exchanges in CCPD occurred while the patient is supine, this increase in effective surface area would account for the difference. We also observed a strong correlation between the peritoneal transport constant (KoA) as a function of intraperitoneal infusion volume (Vip), with the KoA in the supine position being 1.7-fold greater than in the ambulatory positions using comparable volumes 16. The early success of CCPD was aided by the contributions of Dr. Wadi Suki who simultaneously pioneered and adopted this modality of PD 17 and Dr. Richard Fine at UCLA who was responsible for the diffusion of this practice in the pediatric world 18.
The main problem with CCPD was inadequate ultrafiltration (UF) during the very long diurnal cycle due to increased glucose absorption. Not only was UF often compromised, but also the use of highly hypertonic solution resulted in a large caloric load and potential irritation of the peritoneal membrane. One answer to the problem was the development of PD Plus, the addition of an exchange in the middle of the day using either the cycler or a manual exchange with a dialysate bag. This simple modification improved UF, small molecule clearance, and reduced glucose loads 19.
Another challenge was the persistent high incidence of peritonitis. This stimulated many changes starting with external occlusion, a principle we developed using an inexpensive plastic clamp that totally occluded the lumen of the patient line, allowing cutting the line with unsterile scissors to disconnect the patient from the cycler without opening the system 20. This was later replaced with better connectors using outer sleeves, with or without povidone iodine wells to reduce contamination and eventually automated mechanical connectors bathed with UV light.
Today, automated PD (APD) is the predominant modality of PD in North America, with twice as many patients on APD compared with CAPD 21, and in many other parts of the world 22; although the use of APD is increasing worldwide, application in developed countries is greater that in developing countries (42.4% vs. 15.8%). However, the journey to provide full mechanical renal replacement therapy continues. Recently, the search for higher efficiency led me and others to revisit continuous flow PD (CFPD). An interesting historical fact is that CFPD was one of the earliest modalities of PD using two separate catheters 23. The initial pilot studies confirmed the high clearances reported five decades ago by Shinaberger et al. and Diaz-Buxo 24, 25, but failed to consistently provide adequate UF. After much work designing and experimenting with dual lumen catheters and the kinetics of this technique, we decided to shelve the projects until a nonabsorbable, effective, and safe osmotic agent, and easy-to-implant double lumen catheters that provide excellent mixing and minimal recirculation are developed.
My latest interest has been to further develop sorbent dialysis into an effective, portable, simple, and most importantly eco-friendly system for use in PD and HD. I owe much to Martin Roberts for his contagious enthusiasm, great contributions to the first clinically tested sorbent HD system (REDY), and warm friendship throughout the years. My first exposure to the system was during my residence years, both treating acute and home patients. In the early 1980s, I started considering the potential future of sorbent dialysis when “Marty” asked me to try a modified REDY system to regenerate spent PD fluid for high flow CFPD 26. Although the project was eventually abandoned, the foundations for future therapy were established. Renewed interest in sorbent dialysis during the last decade has resulted in various designs for HD and PD systems. Hopefully, some of these systems will bear fruit.
My other passion remains fluid and sodium management, one of the essential factors in delivering adequate dialytic care of both PD and HD patients. Further recognition of the complexities of determining optimal hydration has resulted in a multitude of concepts and devices to quantitate and monitor fluid status during dialysis. The answer will probably require means to establish the ideal postdialytic weight and define the optimal rate and frequency of fluid and sodium removal. Much progress is being made in this arena.
Finally, education is the ultimate means to ensure optimal delivery of dialysis and to generate confidence in delivering this service. Our plea for emphasis on the comprehensive care of the dialysis-dependent patient in the nephrology training curriculum still resonates one decade later 27. The recipients of proper education should include clinicians, patients, regulators, and the community at large. At no time has it been easier to communicate best practices to a large audience than the present.
Throughout this journey, I have been blessed with curiosity, but most importantly, by the generosity of my mentors and peers and the fortune of having been able to participate in so many projects, some of which have improved the lives of thousands of patients and their dear ones. Most innovative concepts are the product of previous science and team work; the more diverse the team, the better the chances for success. I have been quite fortunate to have been surrounded by engineers, physiologists, physicists, clinicians, marketers, and manufacturers throughout my professional life. Each of these disciplines contributed to my development and the implementation of our ideas, and most importantly, to the benefit of our patients.
Jose A. Diaz-Buxo obtained his BS and MD from the University of Puerto Rico with high honors, and his MS from the University of Minnesota. He served his internship and nephrology residency at the Mayo Clinic in Rochester, MN, USA. He has published in excess of 300 peer-reviewed papers, chapters, and editorials, hundreds of abstracts, and national and international presentations. He has served on multiple editorial and review boards. He has been a clinical professor of medicine at the University of North Carolina, emeritus attending at Carolinas Medical Center, and past Chief Medical and Regulatory Officer for Fresenius Medical Care Renal Products Division. He received the National Kidney Foundation Post Doctoral Fellowship Award in 1974 and the American Kidney Fund Torchbearer Award in 1999; is listed in The Best Doctors in America and in the Southeast Region, in Who’s Who in Medicine and Healthcare, Medicine, Science and Engineering; and was an elected member in the Alpha Omega Alpha honorary medical society in 1969 and the Society of Sigma Xi in 1975.