Milestones in the development of peritoneal dialysis


Patrick T. McBride

The first references to the peritoneal membrane have come from the ancient Egyptians who were the first to describe the physiology of the peritoneum. This was performed by the early physicians and this information was recorded in the Ebers Papyrus as early as 3000 BC (Figure 1). Others would attempt to treat kidney problems with blood letting, steam baths and the use of locally produced medications. I will attempt to chronical most of the key innovations in this brief review of the milestones in peritoneal dialysis.

From

Baxter Healthcare Corporation, Deerfield, Illinois.

The early peritoneal dialysis investigators

The first concept of Peritoneal dialysis may have evolved from a novel treatment by the Reverend Stephen Hales, in 1743 , of a patient who was suffering from ascites (1). The procedure was performed by instilling Bristol water and claret wine into the peritoneum through a leather pipe. The patient reacted so violently that the treatment was discontinued. It is interesting to note that she did recover shortly thereafter and it was noted that she was able to walk seven miles shortly after her recovery.

The initial peritoneal investigators looked at the transport of the peritoneal membrane primarily and they did not use it for fluid removal. In Germany, Wegner (2) had determined the absorption rate of various solutions from the peritoneum as early as 1877. Rosenberg (3) in 1919, noted that the fluid in the peritoneum, contained the same amount of urea that is found in the blood. Engel (4) in 1918, demonstrated that protein will pass through the peritoneal membrane. Starling and Tubby (5), described the fluid removal characteristics of the peritoneum in 1894. Orlow (6) in 1895, pointed out that there is absorption from the peritoneal cavity. Tracy Putnam (7), in 1923, suggested that the peritoneum may be used to correct physiological problems.

Others who looked at the clinical application of peritoneal dialysis:
Georg Ganter

The first clinical application of peritoneal dialysis was performed by a Georg Ganter (8) in Germany in 1923. He was looking for a dialysis procedure that did not require the use of hirudin, which was used to prevent blood from clotting, but which was toxic to humans. He refined a technique that had been described by Rowntree and others, to use the peritoneum as the dialyzing membrane, which did not require the use of an anticoagulant. Ganter used a simple hollow needle to instill a sterile physiological solution into the peritoneum. He prepared the solution in large bottles that contained the proper amount of electrolytes with dextrose added for fluid removal. These bottles were then boiled to insure that the bacteria had been removed. He used rubber tubing as a conduit for the fluid to go from the bottle to the needle.

The first patient that was treated with this system was a woman who had renal failure after child birth. Ganter instilled from one to three liters of solution into the peritoneum and let it dwell from thirty minutes to three hours. He continued to do the exchanges until the blood chemistries became more acceptable. He sent the patient home and she subsequently died. Ganter makes note that he was not aware that he had to continue the therapy.

Ganter made a number of important observations on treating patients with peritoneal dialysis that are still valid today. He commented on the importance of adequate access and that it was easy to inflow the solution into the peritoneum but that it was very difficult to maintain adequate outflow because of the use of the needle access. Infection was also noted by Ganter. He stated that this was his most frequent complication of the procedure.

The most important principles of peritoneal dialysis that were identified by Ganter are:
(a) adequate access is of primary importance
(b) sterile solutions will help prevent infection (c) fluid removal is determined by the dextrose concentration
(d) dwell time and fluid volume will affect the solute clearance.
Ganter's work is considered a classic in that he described many principles of peritoneal dialysis that are used today.

Stephen Rosenak

Rosenak and Siwon (9), developed a catheter for continuous lavage of the peritoneum that would help overcome some of the previously described problems with access (Figure 2). Rosenak became very discouraged with peritoneal dialysis because of the frequent incidence of peritonitis.

Wear, Sisk and Trinkle

The next significant event in the development of peritoneal dialysis occurred at the Wisconsin General Hospital in 1936. A group headed by Wear, Sisk and Trinkle (10) performed a peritoneal dialysis on a patient who was suffering from obstructive disease. They were able to maintain the patient on continuous dialysis until the obstruction was resolved. This was a critical step in the evolution of peritoneal dialysis because it demonstrated for the first time that a patient could be safely treated on peritoneal dialysis.

P.S.M. Kop

World War II was the stimulus for research in many areas of medical care. The reason for this interest is that war provides the most difficult treatment challenges in much larger numbers than in peacetime. Also, there is an intense interest in resolving these needs as soon as possible with minimal concern for cost.

The most identifiable demonstration of the value of dialysis was achieved by Willem KolffM.D. (II) who performed the first successful hemodialysis in 1945. The ironic aspect of Kolff's work was that it spawned further investigation into the use of peritoneal dialysis by one of his associates, P.S.M. Kop M.D.

Kop used an integrated system that employed a gravity fill system. He utilized a large glass catheter and latex rubber tubing. The system also utilized procelain containers so that all the components could be easily sterilized. This group treated twenty one patients, they were successful with ten of these treatments.

Seligman, Fine and Frank

Another group at the Beth Israel Hospital in Boston Massachusetts, was directed to find a method to treat renal failure under battlefield conditions. Jacob Fine M.D., Arnold Seligman M.D. and Howard Frank M.D. (12) pursued the application of peritoneal dialysis. Their system was similar to the Kop system. They employed large bottles that were sterilized with the solution in order to prevent bacterial contamination. They employed two catheters so that they would minimize any potential obstruction on the outflow phase of the procedure.

They treated a patient with this system in 1946 who was suffering from acute renal failure that was induced by the use of sulfa drugs. The patient recovered and this is considered as one of the primary milestones in peritoneal dialysis (Figure 3).

Arthur Grollman

Peritoneal dialysis remained dormant until 1952, when Arthur Grollman M.D. (13) described the use of a one liter container with a cap that connected to a piece of plastic tubing. This tubing was then attached to a polyethylene catheter. The catheter was revolutionary because it was flexible in design and Grollman had made some very small holes in the distal end with the use of a heated common pin. He suggested that the fluid be instilled by gravity and that it would dwell for thirty minutes and then it would be drained out into the same container. This technique would be repeated on an hourly basis until the patient's chemistries returned to normal. His work is a classic in that it describes the intermittent method of peritoneal dialysis that we use today. The only difference is that it suggested the use of one liter bottles and that he only performed the procedure on dogs.

Morton Maxwell

Maxwell had been involved with acute hemodialysis at Wadsworth V. A .Hospital in Los Angeles during the latter part of 1950's. He felt that the hemodialysis system was too difficult for the average practitioner to handle. He reviewed the work of Seligman, Fine and Frank as well as Grollman and decided that he would attempt to put together a system to treat acute renal failure. It was necessary for Maxwell to convince a local manufacturer of IV solutions to develop a special peritoneal solution in a special container. He also convinced this manufacturer to provide a plastic tubing set and a polyethylene catheter. Maxwell was looking for a simple system that would be easy to set up and use by a variety of medical personnel. He wanted to prevent infection so the system was designed to require as few connections and disconnections as possible.

The technique was quite simple: instill two liters of solution into the peritoneum, let it dwell for thirty minutes and then drain the fluid into the original bottles. This procedure was continued until the patient's chemistries were normal.

Maxwell performed a number of successful peritoneal dialyses using this method. Dialysis was no longer relegated only to those hospitals that had hemodialysis equipment, it could now be performed in any hospital where the supplies were available and the procedure was understood. Maxwell published his results in 1959 and his work was regarded by the medical community for simplicity and medical significance. It became known as the "Maxwell Technique" for those who would perform peritoneal dialysis later (14).

Paul Doolan

Another group at the Naval Hospital in San Francisco, headed by Paul Doolan M.D. (15), explored the use of peritoneal dialysis as it would be used under battlefield conditions. With the help of William Murphy M.D. , who had worked with the John Merrill group at the Peter Bent Brigham Hospital in Boston, they developed a very unique catheter for long term use. This catheter was made of polyethylene for its flexibility properties, and contained a number of grooved segments that prevented blockage of drain holes. Doolan suggested that this device could be used over a period of time which would suggest chronic usage.

The peritoneal activity at the Naval Hospital did not go unnoticed. A young physician, Richard Ruben (16), who was finishing his tour of duty in the Navy, was asked to see a woman who had gone into renal shutdown. He decided to treat her with the "Doolan Technique". Ruben implanted the Doolan catheter and began to do peritoneal exchanges for a twenty four hour period. The patient's condition improved so dramatically that they were encouraged to continue (Figure 4). The patient's condition deteriorated towards the end of the week and additional dialysis was required. Again, her condition improved so dramatically that Ruben allowed her to spend the week days at home and to continue the treatment on the weekend. This treatment was continued for three months without the need for removal of the catheter. The catheter was replaced once in the seven month treatment period. This appears to be the first chronic treatment of a patient with peritoneal dialysis utilizing a permanent indwelling catheter. As was discussed earlier, chronic dialysis as we know it today, became the focus of renal care in 1960.

Due to lack of hemodialysis resources and funding for care of dialysis patients, peritoneal dialysis was proposed as a alternative treatment by Belding Scribner M.D. to overcome these financial and logistical constraints.

Fred Boen (Figure 5).

In 1960, ScribnerinvitedFredBoenM.D. to come to Seattle and set up a chronic peritoneal dialysis program that would allow patients to be treated at home. Boen had written a thesis on the kinetics of peritoneal dialysis in 1959 ( 17) and it had attracted a lot of attention in the dialysis community. He had dialyzed patients using a system similar to the one that was used by Kop earlier during his time in Holland.

Working with George Shilipetar (18) and others at the University of Washington, he developed an automated unit that could be operated overnight, unattended. This system utilized (Figure 6) 40-liter bottles that were filled and sterilized at the University of Washington, they were then delivered to the patient's home and were returned after use. They also developed an automatic solenoid device to meter the fluid in and out of the peritoneum. Boen attempted to utilize a permanently indwelling conduit that would allow him to insert and remove the catheter between treatments. The continuing complication of peritonitis forced him to abandon this technique. He adopted the intennittent method which was to place a new catheter into the peritoneum before each procedure and remove it on completion of the treatment. This technique was adapted for home use. A physician would go to the house and place the catheter and leave after the procedure had begun. The treatment would last for about twenty four hours, on completion of the treatment, the patient's helper would remove the catheter and the patient would lead a normal life until the next weekend when the dialysis would be performed again. Although the dialysis became quite routine, the logistical support required did not provide for wide spread use of the technique.

Henry Tenckhoff

In 1963, Tenckhoff accepted a position at the University of Washington to continue the work of Doctor Boen. He quickly saw that the procedure would have to be changed if the program was to grow. Tenckhoff's first objective was to find a peritoneal dialysis delivery system that would be easier to use. The patients had a great deal of difficulty in handling the large 40 liter bottles and there was always a waiting period before dialysis so that the fluid could be heated to the proper temperature.

The first approach to developing a simpler system was to eliminate the transporting of the large 40-liter bottles. This was accomplished by installing a water still in the house that would provide sterile water ( 19) .The water was mixed with a peritoneal concentrate to provide the proper dialyzing fluid. The system worked but it was bulky, time consuming and in some cases it was dangerous because of the high pressures involved in the use of the still. Tenckhoff and colleagues also developed a solenoid system that would automatically fill and empty the peritoneum.

The next approach was to employ the use of an inline reverse osmosis (RIO) water treatment system that eliminated the need for the large bottles and the still. The RIO water was mixed with the peritoneal concentrate and the integrated solenoid controller would control the inflow and outflow of the peritoneal solution. This was the prototype for all of the RIO peritoneal machines that would be developed later. Tenckhoff now had a system that was fully automated and easy to use (20).

Russell Palmer (Figure 7).

Palmer had been one of the first to do hemodialysis in North America utilizing the rotating drum kidney. He was looking for a dialysis procedure that did not have the problems associated with hemodialysis. He focused on developing a catheter for long term use. He had been aware of the excellent work of Wayne Quinton in developing the silicone AN shunt for chronic hemodialysis. He asked Quinton to develop a silicone catheter for continuous access to the peritoneum.

Palmer published his clinical experience in 1964 (21) .This was truly a milestone in the development of chronic peritoneal dialysis because it provided continuous access to the peritoneum for the first time (Figure 8).

Tenckhoff saw the value of this concept and he began to look at ways to modify the catheter so that it would be easier to insert and use. He shortened the catheter and suggested two designs, straight and curled. In addition, he added Dacron felt cuffs to help seal the openings through the skin and abdominal fascia. He also developed an insertion tool, which is called a trocar, that was designed to provide easy placement of the catheter. Tenckhoff now had the complete system for doing chronic intermittent peritoneal dialysis.

Norman Lasker

Lasker's interest in treating renal failure was stimulated by his experience at Georgetown University School of Medicine in 1961. Harold Jagers M.D. , the chairman of the department, arranged for Lasker to spend a period of time with George Schreiner to learn to do hemodialysis and to gain experience in clinical nephrology. Lasker developed a keen interest in renal care and especially dialysis. After his training was completed, he returned to New Jersey to set up his practice.

Funding for dialysis in the 1960' s was difficult to obtain, as a result there were few facilities for the care of dialysis patients. Lasker looked for other methods for treating patients in renal failure. He adapted the techniques of Boen, Tenckhoff and Palmer in establishing his peritoneal program. Lasker attempted to simplify the two liter exchange technique by using sterile eight liter containers . This system was simpler but it still required a great deal of labor. He had visited the Seattle program and he had seen the automated systems developed by Tenckhoff; he felt that these systems would be too expensive and too difficult for his group to manage on their own. He recognized that these devices were a great advance over the manual methods but he was still fascinated by the possibility of developing a gravity-fed system.

Fortunately in 1961, Lasker was approached by IRA Gottscho who had set up a foundation in memory of his daughter Carol, who had died of kidney disease. Lasker asked for help in developing a gravity-fed peritoneal dialysis delivery system. Mark Schachter, an employee of the Gottscho Packaging Equipment Co. was assigned to help him design a mechanical system for peritoneal dialysis. The system employed the use of two liter bottles and included the use of plastic reservoir bags so that the system was easy to set up, safe from infection and easy to operate (Figure 9). It was called the "Peritoneal Cycler" (22) .

Lasker moved to Thomas Jefferson School of Medicine in 1967. He found that there were no funds available for in center dialysis and the state would only support home dialysis. He felt that the hemodialysis equipment at the time was too expensive and difficult for most patients to use. He began to send patients home on the "Cycler" as early as 1970. The medical community did not readily accept the device because of the bias towards peritoneal dialysis, but this bias did not diminish Lasker's enthusiasm because he was convinced that this automated system had a place in treating the dialysis patient.

Oreopoulos, who was educated in Greece, had been introduced to peritoneal dialysis during his training in Belfast, Ireland in 1966. He noticed that others were having difficulties not only with the procedure but primarily with the catheter. He had met N orman Deane M.D. , who had shown him a simplified technique for inserting a catheter utilizing the "Deane Prothesis", which allowed the access site to be used over and over again. As a result of this meeting, Oreopoulos began to put patients on chronic peritoneal dialysis. An opening at the Toronto Western Hospital became available in June 1969 and Oreopoulos accepted the position. He was put in charge of a four bed IPD (intermittent peritoneal dialysis) program. Stanley Fenton M.D. had visited the University ofWashington's chronic peritoneal dialysis program. He was impressed with the results that were being obtained with the Tenckhoff catheter. On his return to Toronto, he met with Oreopoulos and they decided to use the Tenckhoff catheter as the access device of choice. Fenton assisted Oreopoulos in adapting the Tenckhoff technique. Due to the space limitations at the Toronto Western Hospital, they began sending patients home on peritoneal dialysis. Oreopoulos had heard about the "Lasker Cycler", and he visited Philadelphia to see how well it worked. He was so impressed that he ordered a number of them and he began to send patients home on the device because of its simplicity and economy.

By the year 1974, Oreopoulos was managing over seventy patients on chronic peritoneal dialysis, which was the largest program devoted exclusively to peritoneal dialysis at that time.

Jack Moncrief and Robert Popovich (Figure 10).

The passage of legislation in 1973 provided funding for all patients who required dialysis treatment. Patients, who were previously not candidates for dialysis treatment, were now entitled to care. This milestone allowed physicians to treat patients who were previously not candidates for the dialysis.

Jack Moncrief had finished a residency in nephrology at Georgetown University and he set up his practice in Austin, Texas. In 1970, Moncrief received a grant from the Texas Rehabilitation to open an in-center dialysis program. The patient population grew very rapidly in those early days and it was evident that the community's needs were not being met. A new facility was built at the Austin Diagnostic Clinic in 1973 to accommodate the increased number of patients who were now eligible for care.

In 1975, Peter Pilcher {Figure 11) was accepted for chronic dialysis at the Austin Diagnostic Clinic. A standard NV fistula was created and his dialysis was attempted. The fistula clotted on the first treatment. It was corrected and again dialysis was attempted with the same results, the fistula would not function. It became obvious that this patient was not a candidate for hemodialysis.

It was suggested that the patient move to Dallas where there was an IPD unit that could treat him. This form of dialysis would require over 60 hours of treatment per week in order to control the chemistries properly. The patient refused to move to Dallas.

This patient was reviewed at the next Research Meeting at the Austin Clinic. It was pointed out that there was no hope for this patient because peritoneal dialysis was not available in Austin. One of the research associates noted that they couldn't let the patient die and that there must be a way to treat this patient with peritoneal dialysis.

Robert Popovich worked out the kinetics of "Long Dwell Equilibrium Peritoneal Dialysis". They also determined that it would take five exchanges of two liters per day to achieve the appropriate chemistries . It was also determined that twelve liters of equilibrated solution must be removed from the patient per day.

The method that they used was to take a standard two liter bottle and attach a simple piece of tubing to it and the Tenckhoff catheter. The fluid would be instilled for a period of four hours and then drained out. This procedure would be repeated for up to five times a day. They later named the procedure CAPD {Continuous Ambulatory Peritoneal Dialysis). They found that they were able to control the patient's chemistries and fluid removal with this very simple technique. The shortcomings of the technique were that infection and protein loss could be complications but it did work.

They submitted an abstract on equilibrium peritoneal dialysis to the Amer. Soc. for Artif. Int. Org. but it was rejected for presentation. Undaunted, they continued to work with the procedure and perfect their technique.

Peter Pilcher was trained to do the exchanges by himself once Moncrief had been able to determine that the solution could be left in the peritoneum overnight without compromise. The patient was dialyzed with this system for over two months and was then transplanted.

Moncrief notes that the protein loss was observed very early in the treatment series. He compared the serum albumin with the protein in the drained solution to determine the protein loss. It became evident that the diet of the patient would have to be supplemented with protein and that other dietary restrictions could be relaxed. They were so impressed with the results that they requested a grant from the National Institutes of Health to continue dialyzing patients with CAPD because it was not covered by Medicare.

Karl Nolph at the University of Missouri, was notified of the progress with CAPD and he was asked to join the group by the National Institute of Health and evaluate the clinical use of CAPD . Nolph had an interest in the kinetics and transport of the peritoneum that had been stimulated by the work of Boen and his collaboration with Popovich on peritoneal dialysis. Nolph's group began to treat patients with CAPD as early as January 1977. They were able to publish their results, which include the Moncrief experience in 1978 {23). The results were promising but the high incidence of peritonitis continued to be a problem.

Oreopoulos was very skeptical of the clinical application of CAPD. Fortunately, Jack Rubin a fonner nephrology fellow at Toronto Western Hospital came to the University of Missouri as an advanced fellow and became involved in the CAPD program. On a visit to Toronto, he told Oreopoulos of the results of the CAPD program at the university of Missouri and noted the therapeutic benefit of CAPD but he also pointed out the problems they were having with peritonitis that appeared to be related to the use of the bottle method.

Oreopoulos's First r;APD Patient

Another milestone in the development of CAPD occurred in 1977. One of Oreopoulos ' s patients , who had been trained on RIO peritoneal dialysis, was re-admitted into the hospital to be trained on the cycler because she was not doing very well on RIO peritoneal dialysis. The patient had an unfortunate fall in the hospital and the staff decided to perfonn manual peritoneal dialysis on her. Fortunately, Canada had begun using the two liter collapsible container for peritoneal (Figure 12) solution prior to this incident. They used a standard "Y" set with the two liter containers and began to perfonn the standard CAPD procedure. The empty bag was used to collect the spent solution and the procedure was repeated every four hours. The patient's condition improved so dramatically the patient was able to ambulate safely. Oreopoulos consulted with Ron Hamade, his local BAXTER salesman, and asked him to find him a piece of tubing that had a spike on one end and a male press fitting on the other. Ron suggested that they use a piece of the tubing that was used on the RIO set, and it worked perfectly.

It was fortunate that Oreopoulos had over seventy patients on peritoneal dialysis. He was able to convert the IPD patients quite rapidly to CAPD and he could evaluate the results on a broad based patient population very quickly. He had the opportunity to evaluate the advantage of using the peritoneal solution in the bag and observe the ease of use of the system as well as comparing the effect of the closed system to the bottle method in controlling infection.

The interest in CAPD continued to grow but it became apparent that if peritonitis could not be controlled, CAPD did not have a future. The focus was now centered on gaining approval in the U. S . for the two liter plastic container so that the closed system advantage could be utilized. It was released by the FDA in October 1978. Once approval was obtained, CAPD began to gain wide interest and acceptance. Shortly thereafter, the treatment was cleared for reimbursement by Medicare.

C.T. Flynn

Another important peritoneal dialysis treatment innovation was suggested by C. T .Flynn, who was the first to propose that renal failure patients who are diabetics, may do better on CAPD.

Flynn noted that utilizing the long dwell time of the dialysis fluid in the peritoneal cavity could be used as a medium for insulin administration. Due to the large molecular size of insulin (5000 MW) it is slowly absorbed from the peritoneum. With this technique, he was able to maintain blood sugars in the nonnal range required for good patient management (24). Prior to this suggestion, diabetics were often excluded from peritoneal dialysis. Currently, over thirty percent of the patients on peritoneal dialysis are diabetic. Intra peritoneal insulin administration has become an importnat technique in treating the myriad complications of renal disease.

The Medicare legislation of 1983, provided for the same reimbursement regardless of home or in center treatment, stimulated the utilization of home training programs offering CAPD .

Other Advances

The basic CAPD procedure was further modified to help control peritonitis. Ultra-violet treatment of the bag spike junction helped to prevent contamination during the exchange procedure. Modification of the container sizes and formulations, further expanded the efficiency of the system. Automated cyclers were developed to accommodate the needs of pediatric patients and those who could not do the normal CAPD procedure (Figure 13) .Recent developments have allowed the patient to disconnect the fluid container between exchanges in order to accommodate the patient's lifestyle and self image requirements.

The future of peritoneal dialysis will surely be directed towards solving the infection, access and other metabolic concerns. The biomedical engineers will continue to produce systems that are easier to use and that are more compatible with everyday lifestyles. Peritoneal dialysis is the closest man has come to developing the true "wearable artificial kidney", the past is still the prologue to the future.

References

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