My Addiction: The Artificial Kidney, The Rise and Fall of Dialysis

THE BEGINNING

In the fall of 1956, I started my first clinical rotation after 2 years of preclinical medicine at the University of Lund, having read and memorized tons of facts in innumerable books. This is different, very different, the first encounter with real patients. I think to most of us who have gone through this, it is a scary moment: I am not a real doctor, just a medical student; will I miss important clues and signs? Am I any good with the stethoscope?

I reported to the Department of Internal Medicine at the University Hospital. Professor Nils Alwall was the attending physician. It was now 10 years since he started his treatment with the artificial kidney in 1946—the first complete dialysis apparatus, one with both dialyzing and easily performed and measured ultrafiltration capacity. I was told that my patient was in her room and I went in, very uneasy, uncomfortably feeling a bit of a sham in my white coat. In the bed was a young woman, semiconscious from preeclampsia with acute rapidly progressive uremia, an almost 100% lethal complication, in her late pregnancy. She had been flown in from northern Sweden by the Swedish Air Force to the only dialysis unit in Sweden. Taking the history of her disease was very brief—she was beyond telling anything. I listened to her heart and lungs; they seemed fine, but I had no particular confidence in the accuracy of my physical diagnosis. As I sat, not knowing what I was now supposed to do, the door opened, a couple of nurses and technicians came in with a gurney and we wheeled her down to one of the two dialysis rooms. I felt a bit wobbly as one of the dialysis staff put in the two glass cannulae in her arm and connected them to the Alwall dialysis apparatus, and a 5-h dialysis began. It took time to adjust to the sight of blood. When dialysis finished, the cannulae were bandaged and left in place with a heparin lock, and my first clinical day came to an end. The next day, one could elicit a few words from her. It was time for the next dialysis. In the middle of the dialysis, she began having cramps and quickly delivered a very vital baby girl. Now there was a lot more blood, almost everywhere. A kind nurse escorted a white-faced young medical student to a chair. After four more dialyses in a 30-day period, urine output resumed and the blood urea nitrogen rapidly normalized, she was sent back home with her baby, and in me the hook was set—the marvel of the Alwall artificial kidney saving two lives!

NILS ALWALL

No one has done more to promote dialysis than Nils Alwall, the son of a small farmer in southern Sweden. He had a PhD in biochemistry and trained in pharmacology and in physiology in Hungary. In the early 1940s, aged 36, he shifted his interest to clinical medicine and began a series of remarkable dialysis experiments, using rabbits for his studies of pulmonary changes in uremia and their reversibility with ultrafiltration with and without dialysis. He then developed the first clinical dialysis apparatus with large and predictable ultrafiltration capacity. It was light-years ahead of the simultaneously developed artificial kidneys in The Netherlands and in Canada, a triumph of considerations of renal physiology and thoughtful mechanical solutions. While others tinkered with less perfect devices, Alwall promoted and developed dialysis in Sweden and in the world. He was a founding father and president of the Swedish Association of Nephrology, the European Dialysis and Transplant Association (EDTA), and the International Society of Nephrology. By 1957, Alwall had dialyzed some 400 patients that then arrived at a rate of two per week, with over 1000 dialyses. I remember him returning from a dialysis meeting in the USA and somewhat wonderingly saying that he alone had treated more patients than all the other attendees together. There was a special drama; the desperately ill patients, mostly the result of surgical complications, were flown in from all over Sweden and also from other countries. A special professorial chair, a very unusual event in Sweden—Professor of Renal Diseases—was created for him in 1957 and he was given his own department of nephrology, probably the first in the world. With that came several new positions, one was a research assistantship and I was the first one to hold it. His nephrology department, with the world’s busiest dialysis unit, was an ideal place to train and physicians came from all over the world. It was an enormously stimulating place to be, with world famous researchers in nephrology and a multitude of ingenious young physicians who came to learn and teach. In a “Festschrift” to Alwall in 1985, there were 64 contributing authors from every corner of the world.

LEARNING CLINICAL RESEARCH AND ACUTE DIALYSIS

I worked with Alwall doing clinical research in the largest acute renal failure program in the world from 1957 to 1962. It was a true vortex for learning with specialists in surgery, infectious diseases, and respiratory physiology that were attached to the clinic and with the extra stimulus from visitors from all over the world. It was the first true intensive care department. The result of our analyses was published as Therapeutic and Diagnostic Problems in Severe Renal Failure, edited by N. Alwall, Scandinavian University Books, Stockholm, 1963. It mapped the horrendous complications in over 1000 patients, most due to surgery problems, and how to overcome the difficulties in diagnosing them and how to treat them. Those patients were shunned by many; Alwall’s saying was “These patients are too sick NOT to be operated on.” He had an open arms policy in accepting these very sick patients; none was denied access.

TO AMERICA—THE SCRIBNER SHUNT

In 1962, I received a scholarship to spend a year as an intern at Bethesda Lutheran Hospital in St. Paul, Minnesota. The last 3 months of the internship was elective and I went to Seattle and spent several months at Belding Scribner’s dialysis unit learning the technique of chronic dialysis, then into its second year of development. As an anecdote illustrating the explosion in dialysis development, in 1959, a high school classmate of mine was admitted to Alwall’s department with acute renal failure from glomerulonephritis. He never regained renal function and, in the pre-shunt era, died after 180 days of dialysis. He was then the longest dialysis survivor in the world. Three years later, while at Scribner’s clinic, I met Robin Eady, then in his second year of dialysis for irreversible glomerulonephritis. He is still alive over 50 years later! The hook was planted deeper. I ran an acute dialysis unit at the Bethesda hospital until the end of 1964 and I worked with the renal transplant team at the university participating in their research.

BACK IN SWEDEN—THE RISE OF CHRONIC DIALYSIS

At the end of 1964, I returned to Sweden as an attending physician in Alwall’s department. The department trailblazed chronic dialysis in Sweden and it was very exciting to work there. The dialysis technique was refined, the various problems in the chronic patients (anemia, neuropathy, and bone disease) were analyzed, and therapeutic maneuvers developed. Disposable dialysis filters and safe automatic dialysis delivery systems were developed with the newly founded Gambro Company and tested clinically. We, thus, with many other centers, participated in clarifying the many new and unique metabolic problems of chronic dialysis and how to solve them. These years were exciting discovery and trailblazing years and they bore fruit. The first dialysis and transplant registry by the EDTA in the early 1960s reported that the first-year dialysis mortality dropped from about 50% in the early 1960s to 10% 10 years later. The first US report of 302 chronic dialysis patients from 1969 reported a 12% first-year mortality.

UNIVERSITY OF MINNESOTA: TRANSPLANTATION

In 1967, John Najarian succeeded Owen Wangensteen as chair of surgery at the University Hospital in Minneapolis. Najarian came out of the trailblazing transplant center at Moffat Hospital in San Francisco and made it his main work to develop the small Minnesota transplant program into a world-class operation. This necessitated the development of a forceful dialysis unit—an absolute requirement for a transplant program. I applied for and got the new position as chief of dialysis and moved to the University of Minnesota hospital early in 1968. There was an explosive growth in the dialysis unit, from a two-bedroom operation run by urology residents to a superactive 10-bed unit accepting several patients a week. The technique was developed quickly, resuscitating the very ill patients, and improving them so that they could withstand the many invasive diagnostic tests and operations necessary for their transplant.

There followed 13 years of intense research resulting in approximately 300 articles. A special system for hemodialysis of newborns and very small children was developed. It consisted of a small shunt, dialysis filters requiring only 15 mL to prime, weight monitoring during dialysis, accurate to within 10 g, a formula to use precise blood and dialysate flows to avoid over- and underdialysis, and a system using mannitol to abolish any osmolality changes during and between dialysis. This was a collaborative effort; Ted Buselmeier, my associate, and Michael Mauer, a pediatric nephrologist, were important contributors.

For the first time, large-scale dialyses of patients with diabetes were undertaken. It was regarded as contraindicated due to the poor results of others. The regulation of blood sugar in the functionally anephric diabetic patients was refined, and intraperitoneal insulin in peritoneal dialysate was introduced in 1971 and quantitated with addition of tracers. The work in both acute renal failure and with dialysis of diabetic patients was more enhanced by work with Eli Friedman, who became the great proponent for treating the patients with diabetes as all other patients. The dialysis of patients with diabetes became of worldwide interest. Rashad Barsoum with a whole team came from Egypt, Heitor Borges came from Brazil, Caesar Pru came from Venezuela, von Hartitzsch came from New Zealand, and Francisco Rodriguez came from Spain, to mention a few.

Ted Buselmeier studied intrapericardial steroid infusion in pericarditis and developed new arteriovenous shunts and improved the operative technique for fistula formation. Ultrathin dialysis membranes and new disposable dialysis filters were developed with the new dialysis equipment manufacturers. Hemolysis problems from dialysate contamination were discovered and cured by ascorbic acid addition to the dialysate. Perhaps the most important contribution was the formulation of the unphysiology hypothesis, that many of the serious complications occurring in hemodialysis patients is not so much caused by toxins but by the intermittency of the procedure that brings havoc to the interior milieu. It was first formulated and studied in 1973 and developed over the next 5 years. Its worth has been well proven by the superior results of quotidian hemodialysis now rapidly expanding. About half of the articles analyzed problems in transplantation—that effort mainly led by Richard L. Simmons, by far the best brain in the transplant center. Although not strictly being in the artificial organs field, it resulted in remarkable improvements, trailing only those achieved in dialysis. In 1964, when I first followed renal transplantation at the University of Minnesota, then performed only in young patients with glomerulonephritis, the death rate in the first year was 90%. Upon leaving in 1981, it was around 5%, now in aged patients, over one-third with diabetes!

HENNEPIN COUNTY MEDICAL CENTER AND ETHICAL PROBLEMS

In 1981, a new chief of medicine came to the University Hospital. He was a nephrologist without any background in dialysis. He found clinical work of dialysis of no interest or importance. “When I make rounds in dialysis, I put on my roller-skates” was his explanation when withdrawing residents and students from learning dialysis. This peculiar disdain is widespread in nephrologists who prefer antibodies to patients, screwy looking glomeruli to real faces, and how potassium moves in the turtle to difficult electrolyte problems in the acutely ill. It is a continuous problem that bedevils dialysis in the academic setting and, thus, in fellowship training. One of Alwall’s successors voiced her absolute uninterest in dialysis, “I am not a washerwoman.” Of course, it is common practice by those who are mediocre, or not even that, to bad-mouth and downgrade excellence in others or ridicule interest not in line with their own. I would not work in such an atmosphere and moved to Hennepin County Medical Center in Minneapolis at the invitation of Fred Shapiro and Alvin Schultz.

My main research there switched to empirical analyses of ethical problems in dialysis. I encountered early a number of patients at the chronic dialysis unit at Hennepin who decided to discontinue dialysis and die, a problem not encountered in the relatively young and healthy patients accepted for transplantation at the University. It was until then an undescribed problem. By a review of all deaths in the unit, it was clear that halting dialysis was secondary only to cardiovascular disease as a cause of death in chronic dialysis patients. The first publication about halting dialysis appeared in the New England Journal of Medicine in January 1986 and resulted in a phoned death threat by the Army of God. They had a bullet with my name on it they said. I advised them to make sure their first bullet hit properly as I had a number of gold medals from the Swedish army attesting to my skill in hitting man-sized targets with all sorts of small caliber guns. I have never been shot at, and thus have not had the opportunity mentioned by Churchill, that one of the most exciting things one can experience is to be shot at but missed. There followed over 20 articles and two books addressing the problem of stopping treatment, since then recognized everywhere. The first publication met with two different responses in letters from physicians, criticism that it was a terrible betrayal of the Hippocratic Oath, the other that it was a relief to bring this into the open for study, discussion, and improvement.

The second ethical problem I discovered when I analyzed acceptance rates to dialysis and transplantation and found clear evidence of rationing by age and gender in dialysis and also by race in transplantation. This was described, in 22 articles, two books, and well over 20 presentations between 1984 and 2003. I got very severe criticism, bordering on abuse, for this description of a less than perfect brotherhood, but the problem—that still exists—has since been described by many others around the world; young, rich, white men everywhere have preference. Letting skeletons out of cupboards raises eyebrows and stokes anger.

KAROLINSKA INSTITUTE/UNIVERSITY OF ALBERTA: THESIS OF ETHICAL PROBLEMS

In 1986, I moved back to Sweden as Chief of Nephrology at the Karolinska Hospital in Stockholm. In 1990, I moved to the University of Alberta in Canada. Most of the work was follow-up on large numbers of diabetic patients on hemodialysis, continuing the examination of stopping dialysis, and following these dying patients to try to improve their care and make it more comfortable and less stressful to all. Lew Cohen from Massachusetts was an important stimulator of this in his USA-Canada-wide cooperative research effort. I also continued to study the injustice in selection to dialysis in the USA, Canada, and Sweden. Together, the studies and descriptions of these ethical problems in medicine culminated in my PhD thesis “Giving life—Giving death. Ethical problems in high technology medicine” in 1988.

There were also analyses of vasoactive and stress hormone changes in dialysis, led by Ingegerd Odar-Cederlof. A very exciting interlude were the 4 months as visiting Professor of Nephrology at the University of Cairo, working with Dr. Rashad Barsoum mapping the epidemiology of renal failure in rural and urban Egypt. Diabetes was more common than Schistosoma! About 150 articles were published between the years 1986 and 1997.

THE FALL OF DIALYSIS

The development of the shunt in 1960 suddenly opened the floodgates of chronic dialysis. All over the world, people struggled to meet the demand both by the number of patients and improving the survival that immediately filled every dialysis machine the moment it was installed. Business leaped to the assistance and large companies were established and grew into a billion-dollar industry. As people struggled to accommodate an endless number of patients, one way was to shorten the dialysis time so a nurse and machine could treat more patients. There then occurred an unfortunate marriage of business interest and a single-minded mathematical approach to dialysis, the Kt/V. Several smart mathematically oriented physicians, with little or no physiological thought, simply stated that we could just increase clearance and shorten dialysis time and the patient will then receive the same dose of dialysis. A Kt/V of 1.2 was “adequate.” It was of course honey to the ear of those who ran dialysis for profit; time is money. So poor research without any physiological considerations and business considerations took the place of careful clinical research. The regulation of the most important uremic toxins, water, sodium, phosphate, and beta-2 microglobulin, bear no relation to Kt/V. All these toxins need time, with very long dialysis hours for removal because of the slow movements of these substances in the body during dialysis. As a consequence, dialysis time was successively shortened from 12 h to 3 h thrice weekly, from 1970 to 1987. The first-year mortality rose in proportion to the shortening and increased 250% from 10% to around 24% and has there remained. Meaningless bureaucratic attempts by well-meaning committees and nephrology associations focused on how to treat symptoms: give erythropoietin for anemia, fill patients up with phosphate binders, use antihypertensives to achieve an arbitrary blood pressure. None addressed the real problem; dialysis has become too short and too brutal. You cannot remove a volume equal to all circulating blood water in 3 h in 60–70-year-old patients without doing serious harm to them. Hypotension during dialysis has become a major problem dealt with by vasoactive substances or complicated sodium grading schemes. Witness the old dialysis patients after dialysis in Trendelenburg’s position and either drinking salty broth or receiving intravenous saline in the dialysis waiting room. Absurdly, the fluid, too quickly removed, is now poured back in! As a result, we are left with anorexic, malnourished, arthritic patients, hypertensive between and hypotensive during dialysis, and with a death rate three times that in the 1970s, and that is worse than for most cancers.

AKSYS AND DAILY HEMODIALYSIS

In 1997, while on a sabbatical studying biostatistics at Wake-Forest University in Winston-Salem, I was invited to be the medical director at a small company in Lincolnshire, north of Chicago. Rod Kenley started the company with private money. He had been very impressed by the results of daily hemodialysis of Umberto Buoncristiani. The company was developing a new hemodialysis machine, to be used daily in the patients’ home, the PHD—personal home hemodialysis. It incorporated ideas from the 1970s by Umberto Buoncristiani, Perugia, Italy and particularly solutions proposed by Zbylut Twardowski, Krakow, Poland, and, later, the USA.

For me, it was a natural closing of a circle that had begun 25 years earlier with my formulation of the unphysiology hypothesis. The PHD machine would make the most physiologic dialysis, quotidian hemodialysis, a practical reality. I stayed with the company until retirement in 2006. Much of the work was to deal with the FDA to get the machine approved, which was in 2002. Much of that credit goes to three veteran clinicians, researchers, and trailblazers in home hemodialysis: Chris Blagg at the University of Washington in Seattle, Zbylut Twardowski at the University of Missouri in Columbia, and John Bower at the University of Mississippi in Birmingham.

The main effort of my research, that continues, was cooperative large analyses of quotidian hemodialysis, and, since 1997, another 80 articles have been published. Many dealt with quantitating quotidian hemodialysis, a careful international cooperative effort of quantitation of phosphorous and beta-2 microglobulin dynamics in dialysis by collection of all dialysate where Ingegerd Odar-Cederlof in Stockholm, Chris Blagg in Seattle, and Todd Ing in Chicago were important participants. My research has also involved the evaluation of factors associated with survival in quotidian hemodialysis. The most important leaders have been George Ting at Mountain View, California, trailblazing short daily hemodialysis during the day, and Robert Lockridge at Lynchburg, Virginia, leading the effort of long night home hemodialysis. They have been true heroes in their effort to improve the dismal state of dialysis, in the face of huge administrative, bureaucratic, and political obstacles. Our most succinct finding has been that dialysis, with a weekly stdKt/V of 2.4, accepted as “adequate,” is grossly inadequate. In close to 200 patients followed up to 10 years on quotidian hemodialysis, there is a continuous survival improvement at least up to a stdKt/V of over 5.1, possible only with over 36 h dialysis per week. Long night dialysis has a survival rate four times that in age-, gender-, diagnosis-, and race-matched patients on thrice-weekly patients in the USA. The survival of patients on short daily hemodialysis is two times better.

BIOSKETCH

Carl Kjellstrand got his Nephrology training at the University of Lund with Nils Alwall 1957–1964. He has published over 500 articles, edited 21 books or symposia publications, and 386 abstracts, of which 287 were selected for presentation. He has been Professor of Medicine and Surgery at the University of Minnesota, Professor of Medicine and Bioethics at the University of Alberta, Canada, and was listed in the “Best Physicians in the USA” 1982–1995.

He is an Adjunct Professor of Medicine at the State University of New York at Brooklyn and Clinical Professor of Medicine at Loyola University, Chicago and Docent at the Karolinska Institute in Stockholm. He is an honorary member of the Peruvian Society of Pediatrics and Nephrology and the Venezuelan Society of Nephrology. He is a fellow of the American College of Physicians and the Royal College of Physicians and Surgeons, Canada and is a life member of the Asian Pacific Society of Nephrology. He has been invited as a visiting professor/lecturer at over 400 national and international meetings and academic institutions.