Reflections on My Lifetime Teacher: Dr. Willem J. Kolff

It was July 1956 and I was ready to start a research fellowship at Cleveland Clinic Foundation (CCF) in Cleveland, OH under Dr. Willem Kolff (Fig. 1). As a Japanese exchange fellow, I was excited but scared to be working with such a prominent researcher. In 1944, he had invented the first clinically successful rotating drum artificial kidney (RDK) 1 (Fig. 2). Drs. Willem Kolff and Satoru Nakamoto in July 1956. First clinically successful rotating drum artificial kidney by Dr. Kolff in 1944. Dr. Kolff was born on February 14, 1911 in Holland. He graduated from the University of Leiden Medical School in 1937 and received his PhD from the University of Groningen in 1946. He married Janke Huidekoper in 1937 and they had five children. In 1941, Dr. Kolff worked at an 80-bed city hospital as a junior physician in Kampen, Holland and was assigned to four beds on the medical floor. One of the patients was a young man dying of end stage renal disease (ESRD). The patient was an only child and his father had died years earlier. His aged mother visited him every evening after working at the farm. Dr. Kolff had to tell her that he could no longer help her son and he would die soon. He felt he was worthless. It was then he realized he needed to find a solution to prolong the lives of patients with ESRD. Dr. Kolff thought if he could remove uremic toxins and body fluids that were accumulating in such patients with an apparatus, then the patient would be able to live longer. He paid a visit to biochemistry professor Richard Brinkman at University of Groningen, who was studying osmosis using cellophane membranes. He suggested to use it for dialysis. Dr. Kolff conducted an experiment using 250 mL of blood containing 200 mg/dL of urea in a piece of cellophane casing 5 cm in diameter attached to a wood board. He then submerged the casing in a rectangular container filled with normal saline and shook it up and down by hand. To his surprise, within 5 min almost all the urea was removed. He then calculated that he would need a 20-m cellophane tube to make an effective artificial kidney (AK). With that data, he asked for technical help from an engineer H.Th.J. Berk who was the director of an enamel company. They had constructed a few AKs without success and then invented the RDK in 1944. They wrapped 20 m of cellophane sausage casing on the drum which operated at 28 rotations/min. It was partially submerged in a receptacle containing 100 L of normal saline. The cellophane tube filled with the patient's blood would come in contact with the saline solution. To prevent twisting of the cellophane tube at the connecting joints to the drum, he adapted an old Ford car water pump. One drawback was that fluid could not be removed by hydrostatic pressure because the cellophane tube was not protected to tolerate pressure. The fluid was removed by osmosis adding a large amount of glucose in dialysate. Consequently, many patients developed hyperglycemia and needed insulin therapy. Between March 1944 and July 1945, Dr. Kolff conducted experimental dialysis with the RDK on 15 ESRD patients in Holland and none of them survived. The first survivor was a 67-year-old women who was treated with dialysis on September 11, 1945. He saved her because of his firm conviction regarding equality of the human race. Close to the end of World War II, he had constructed 4 RDK which were stored in Kampen. After the war, he donated one each to British Post Graduate School in London, Mount Sinai Hospital in New York City (NYC), and the Royal Victoria Hospital in Montreal, Canada. A fourth one disappeared into Poland. In 1947, Dr. Kolff was invited by Dr. Isidore Snapper to give a talk at the Mount Sinai Hospital in NYC. He received a $300 honorarium. Dr. Snapper introduced him to the Brigham and Women's Hospital in Boston. Dr. George Thorn, Chief of Medicine at Brigham and Women's Hospital recommended him to the Arts and Science Society and at Dr. Thorn's request Dr. Kolff was made an Honorary Member. That membership carried a reward of $3600. He and his wife decided to travel around the United States for 3 months. Upon their return to Holland, Dr. Kolff decided to immigrate to the United States so he and his children would have greater opportunities for success. In 1949, he again visited the United States and met Dr. Irvine Page at the newly expanded Hypertension Research Institute at the CCF. He saw this as the opportunity he had dreamed about and applied for a position. He was hired. In 1950, Dr. Kolff started to work at CCF. From January 1950 to May 1956 all dialysis sessions were performed with the RDK at his laboratory. However, there was a logistical problem transporting the patients to and from the laboratory. There were three steps and a 90° angle between the sixth floor of hospital and the sixth floor of the research buildings. It was impossible to carry the patient on a stretcher. Thus, two fellows carried the patient in their arms to get there and back. In early 1950s, no nurse or technician was available for dialysis and the fellows did everything for the dialysis procedure. This included checking the patient's vital signs, weighing each chemical in a paper bag, and making the dialysate. After dialysis, the fellow cleaned the dialysis tank and the room. The routine dialysis was 6 h and dialysate was exchanged every 2 h. The standard dialysate contained sodium 138, chloride 103, bicarbonate 35, calcium 5, and magnesium 1.5 mEq/L. Only the potassium concentration varied from 5, 3.7, 2.5, and zero mEq/L depending on the patient's potassium level. To avoid mistakes making the dialysate three steps were taken. The first one was an iron rule. Only one fellow made the dialysate and collected each empty paper bag at the end of dialysis. The second was that several drops of the patient's blood was mixed with dialysate in a small test tube which was centrifuged; no hemolysis meant the right concentration. The third was a fellow who tasted the dialysate for salt. No osmometer was available then. In 1953, Dr. Kolff got an idea of performing an arrested open-heart surgery by injecting a high concentration of potassium chloride (KCl) into the base of the aorta after clamping it 2. Dr. Donald Effler, then Chief of Thoracic Surgery, did this experiment on dogs and it succeeded. Then, he applied it to a patient. After connecting a patient to a heart-lung oxygenator and clamping the base of aorta where he injected the KCl solution, the heart stopped and the open heart surgery was performed on an arrested heart. As soon as the clamp was released, the heart promptly restarted its normal regular beats. This revolutionized open-heart surgery around the world. While the dialysis records from 1950 are missing, a total of 62 dialysis sessions were done with the RDK from January 27, 1951 to May 23, 1955 at Dr. Kolff's laboratory. It was very cumbersome and time consuming to assemble the RDK, so it was rarely used at other hospitals in the nation. He recognized the need for a disposable, ready-made AK. He got the idea of making a disposable twin coil kidney (TCK) (Fig. 3) from the “Pressure Cooker Kidney” made in 1953 by Drs. W. Inouye and J. Engelberg 3. In 1953, he invented the TCK with help from fellow Dr. Bruno Watchinger from Vienna, Austria and Dr. Victor Vertes from Mt. Sinai Hospital in Cleveland 4. He bought a sewing machine for $100 from the Bobbie Brook's garment manufacture in Cleveland and an engineer adapted it to sew two layers of plastic window screens with two 10 m lengths of cellophane tubing in between. The mesh was then coiled around an empty 10 cm diameter juice can. The initial TCK was made by a technician at his laboratory (Fig. 4). The TCK was sterilized with ethylene oxide gas and aerated for several hours. A Sigma motor was used to pump the blood inside the cellophane compartment and another circulating pump below the dialysate tank would pump the dialysate through the plastic mesh. Because of the tight compartment created by sewing the plastic mesh, it was possible to use a pump to circulate the blood and, therefore, remove fluid by hydrostatic pressure. Disposable TCK invented by Dr. Kolff in 1956. A technician weaving TCK at Dr. Kolff's laboratory in 1956. On May 27, 1955 the first dialysis was done with the TCK and thereafter all dialyses were done with it. From May 27, 1955 to the end of 1957 a total of 255 dialyses were done. As the number of dialysis sessions and patients increased rapidly, in the middle of 1956 a room in the hospital was assigned to dialysis and two dialysis technicians were hired. The obvious next step was to patent the TCK. Dr. Kolff requested permission from the CCF administration to do it but it was denied. He then contacted the Baxter Company in Chicago, a reputable commercial medical device company, to mass produce the TCK. In the agreement, Baxter would not pay cash but give him one free TCK per every two purchased. The first commercially available disposable AK became available in 1956. Baxter packaged the product so that a 100 L stainless tank and the Sigma blood pump were included with the first purchase. The price of a TCK was $60. This prompted worldwide use of the TCK; however, the interest dwindled due to lack of knowledge in working with it. With Dr. Kolff's help, Baxter started a training program to help physicians around the world to be able to treat their patients safely. In the decade of 1950–1960, it was estimated that 50 000–90 000 patients died of ESRD yearly in the United States. Only one dialysis machine was available in all dialysis centers in the nation including CCF. The TCK had two separate and distinct blood channels, so a fellow, Dr. Haakon Ragde, got the idea of using each individual compartment to dialyze two patients at the same time 5. However, this maneuver reduced the efficiency of the TCK in half. From this, I got the idea of dialyzing two patients simultaneously in 1962 by using two separate TCK holders connected to the original dialysate circulating pump. Thus, two patients were dialyzed at the same time provided the dialysate was refreshed every hour. As cellophane's pores will not permit bacteria or virus to cross, there was no fear to transmit a disease from one patient to another. In the decade of 1960–1970, there was a preoccupation with the increasing number of the patients who developed ESRD. In 1960, Dr. Belding Scriber in Seattle recognized that permanent access to the blood circulation would be necessary if we were going to attempt to treat those patients. To solve that problem he, with the help from engineer Wayne Quinton 6, created a plastic arteriovenous (A-V) shunt (Fig. 5) to be placed in both the radial artery and cephalic vein of the forearm above the wrist that would provide chronic access. It worked in spite of the opinion of the skeptics. This device made possible the start of chronic dialysis and later kidney transplantation was possible. Dr. Scribner was a longtime friend of Dr. Kolff. When I was sent to Seattle for 1 week to learn the technique, Dr. Scribner kindly invited me to stay at his home. Arteriovenous shunt by Dr. Belding Scriber in 1960. In 1960, Dr. Scribner started repeated dialysis using the Skeggs-Leonard flat kidney 7. He attended the first International Nephrology meeting in Prague, Czech Republic. On the way home, he visited Dr. Kiil in Sweden who invented a flat AK in the late 1950s 8. As the Kiil kidney had a low blood flow resistance, it could be operated without a blood pump. Dr. Scribner thought it was an ideal AK for repeated dialysis. He bought it but it was too expensive to send it by air cargo. He exchanged his airline ticket for a boat ticket. Upon arriving in NYC, he called and told Dr. Kolff that he bought an ideal chronic dialysis kidney from Dr. Kiil. In 1960s, it was estimated that 90 000 patients died of ESRD every year in the United States. It was technically and financially prohibitive to dialyze that many patients at the dialysis centers. A home dialysis program was started to keep more patients alive. It started in Seattle in 1961 and in Boston in 1964 9. In January 1975, the National Dialysis Registry reported that 12 977 patients were on chronic dialysis. Of those, 3712 patients were on home dialysis. At CCF, the first patient started home dialysis in June 1966 and three other patients started in the same year. From January 1967 to December 1973, a total of 125 patients were trained and started on home dialysis at CCF 10. Dr. Kolff started morning conferences promptly at 8:30 am and ended at 9:00 am. All fellows, technicians, a secretary, a test tube washer, and even visitor(s) had to attend on time. The fellow who did emergency dialysis during the night was excused. For the first 5 min, each fellow took a turn and presented interesting subjects not necessary related to medicine. On my turn in 1964, I spoke about the newly constructed Japanese bullet train. Then, the fellow on call reported his activities during the night. The rest of the time was used by Dr. Kolff to discuss that day's research activities and he assigned each fellow his duties. One morning, a very distinguished visitor showed up at 8:35 am. Dr. Kolff made him aware that he was late and he apologized. He was an eminent professor of medicine at a famous medical school in NYC. Dr. Kolff established the Department of Artificial Organs in 1958 which was divided into three sections: The first was the clinical section which took care of patients including dialysis. In 1950s, the fellows were Shigeto Aoyama, Maurice Black, Masaktu Shibagaki, Visth Sitpriza, and Satoru Nakamoto; the second was a total artificial heart project with Drs. Ed Miller and Ted Akutsu as surgeons; and the third the heart and lung oxygenator project for open-heart surgery operated by two technicians. Dr. Kolff hired Dr. William Kelemen in 1957 as a clinical associate. Since then Dr. Kolff made ward rounds every Monday and Thursday morning. His main interest was the construction of a total artificial heart (Fig. 6). He employed an engineer, Steven Topaz, to assist with the Artificial Heart project. After moving to Utah in June 1967, he continued the Artificial Heart project in collaboration with Dr. Robert Jarvik where the first artificial heart was implanted in a human. Total artificial heart project by Dr. Kolff in 1961. Dr. Kolff emphasized the futility of basic experimentation unless it led to an advancement in the treatment of humans. This was the kind of pragmatism that guided my teacher. However, he would not discourage ideas of young investigators. That is why in 1961 a fellow, Dr. Jerry Rosenbaum, and I told him about the idea of adsorbing urea using a sephedex gel and he allowed us to do the experiment which failed. He told us that a experiment had and he us to do it. Jerry to his home in in 1962 and in making an device It became commercially available and was for patients who had an of or which were to and be removed by dialysis. Dialysis in the world. At CCF in a total of dialysis sessions were In to keep each patient's dialysis in Dr. Kolff invented a Dialysis in 1956 (Fig. containing for each dialysis on each patient. for each in each one could all the of patients to the was used an to the made it to to the and to I called it a Dialysis invented by Dr. Kolff in 1956. Dr. Kolff was an and When I attended the meeting of the Society for Artificial Organs in City in I that Dr. and his at the Brigham and Women's Hospital had done successful kidney in 1956 with later from related and chronic dialysis the ESRD patients they had many clinical including of water and potassium which an emergency dialysis. In the middle of 1962 after their on ward I to Dr. Kolff and suggested that we start a kidney I thought the of RDK, he would us on of the dialysis. To my surprise, he with me and called his longtime friend Dr. and made an to send me to Boston to the A few I to Boston for 10 and Dr. me the of kidney On the first I was to a middle aged man who had a kidney was in the with his After from Dr. Kolff and I The first was to the kidney in the nation were all Dr. Kolff Dr. who had done renal surgery He and another Dr. did kidney Dr. Kolff and I would provide the clinical care of the patients and after transplantation and the related Dr. Donald would do the The first meeting took on 27, decided not to live kidney we got with kidney From to total body was used by in In 1960, was first used by At CCF in the 1960s, the were and Only the first patient received to the To make a of and in was developed by In was used for the first time by At CCF, the first kidney was done using a on January on a who on January The second kidney was done on January on a man who died on January 23, on the first related kidney was done from a mother to a and the for many years without From January to the end of a total of related and kidney were performed In I received from Dr. in Boston and Dr. in had trained at Brigham and Women's They the of kidney were so that they were going to the The of was to I told them kidney program is so that we are to the I then and realized after their dialyzed only the increased 100 They a as we continued to dialyze the up to 4 if the did not Then, the was done to its we continued dialysis. the was removed. I then is not to Thus, a amount of it was dialyzed and was my Dr. William that is to and is partially The second kidney meeting was on and the main subjects were as Because of interest on the of and all patients had it on to the of related live and and the will be in the for and then to a room. The needed to care The third kidney meeting was on As we had successful kidney from it was decided to for of from The were to be removed in the room at each To in I made a small container from a with the help of machine (Fig. A man who had a kidney on January 14, 1964 had for years with normal renal and then died of At that he was the kidney survivor in the world. A small sterilized to carry a kidney from other The fourth kidney meeting was on December 1964 to discuss for from the hospitals and to them to CCF. asked the to remove from the of main of was not related to and this was was so we asked for When we called the it an were at the It became the evening At the CCF administration was not about this and thought we called the for of work started with the of the CCF renal transplantation in the Cleveland on May On 5, the of was to kidney transplantation using That was of from the and had worldwide circulation and Because of success with kidney the of from other hospitals became a In to the to other Dr. and I attended their to them and request their help in this In Dr. Kolff a (Fig. that many would carry the in their invented by Dr. Kolff in In the National of established a to a for kidney The of the included Dr. from Dr. from Dr. from Dr. from Dr. from Dr. Donald from and from The first asked Dr. Kolff to be a but he recommended me because I had the The initial of the were very and the that between of the The three from to The September of Medical World the famous that provided the patient care at CCF. are and were to do The Medical World showed of Drs. Irvine world Willem of the George a and of artery a who became the of of and an on and When I became a research in Dr. Kolff took me to the a for to discuss a research project as there were too at his The had a small where a was had a of and at a One was that in the middle of we the of kidney we at a of In the National Registry was in to of in the of In to transporting to the a was The first successful from Dr. in 1967 by including Dr. of the CCF In those the used in this was of the kidney by air in a container to be as a As chronic dialysis had in 1964 the five hospitals in the nation and 000 each for chronic dialysis They were the University of under Dr. Brigham and Women's Hospital under Dr. University in under Dr. George the University of Medical School in under Dr. and Dr. Kolff at CCF. However, the CCF administration it. As Dr. Kolff did not this to to other in other he invited his fellow Dr. Victor Vertes who was at that time Chief of Medicine at Mount Sinai Hospital in The Dr. Kolff's and the was to Dr. In Dr. Kolff was allowed by CCF administration to a of 000 from the Foundation to chronic dialysis at the CCF. It was and he established a chronic dialysis Dr. Kolff me and clinical of the AK. I and him as my teacher. His was and his children called him He me One such was to have time for the no at He the He emphasized the of When he started at CCF in 1950, he was not making for his and had to from the The four and attended the University School in OH and in and became his right he was a This wood with a saw in his He became a After in the in In June 1967, Dr. Kolff was invited by his longtime Dr. the Chief of at the University of Utah Medical School in City to his At the CCF, his laboratory was only of the floor research Dr. a floor Research to a of artificial research including his artificial heart He and the CCF in June I to him but he me to stay to the Dialysis and that he and I had became but He had a with a two in in of Cleveland and his there After moving to Utah in 1967, he had visited the or I provided him from and to the He at His visit to the was in and it was his stay at my (Fig. Dr. Kolff at my home in for the time. Dr. Kolff's be in his as as the fellows who trained under I will a After a year fellowship in 1960, Dr. to the University of and a PhD in He to in 1964 and became an at University Medical School as as Chief of after a year fellowship in Dr. Jerry who to and invented his in after 3 years in medicine at CCF and a year fellowship under Dr. Dr. to in 1962 and was the first He introduced dialysis and kidney after a year of fellowship in Dr. was invited to Clinic in New to start a dialysis and He was in the and started the in for the National and after a year fellowship in Dr. George became a professor of medicine at University of Medical School in and the of at Dr. Kolff me three The first one was a of a of He me this he for The second one was an by his patient under Holland. The the in and had an with the of one was a 6 by 5 by of on the Kidney” (Fig. which was made for Dr. Kolff in by his The man on the is to be Dr. Kolff made only 10 one of which was to three are at room in and of Dr. Kolff. Dr. Kolff's made 10 of on the Kidney” for Dr. Kolff who me Dr. Kolff had received a total of and and 12 In 1964, of University of in the from in at the from the in in as one of the 100 of the in the of and in the and Foundation He more including 5 and 6 in Dr. Kolff from the University of Utah in and to in to be to his son and his Dr. Kolff continued to be invited for not only in the States but In June he to at at the of where his son and his I called him or a the and we had exchanged every year. I have 15 and 5 from He on February 11, at the of He was so at the the there got 3 after his and his I have to have Dr. Kolff as my and at CCF for That was the of a medical and I am to have at the of it with my Dr. Willem Kolff. I am very for his to me as a research fellow in me to a research in and a physician in 1961. I in May after years of to CCF. I that Dr. Kolff's he was about his He told me that he was that and cellophane were he could not the RDK in 1944. Satoru Nakamoto was born in in After received his medical at Medical School in he and in New York and Cleveland, He as at the Cleveland Clinic Foundation from 1961 his in