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

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Pioneer Series Editorial

My Addiction: The Artificial Kidney, The Rise andFall of Dialysis

In 1956, over half a century ago, I saw my firstdialysis. It is difficult to believe that any other specialtyin medicine could have offered a more stimulating,exciting, or rewarding experience then being amember of the first generation of clinical dialysis phy-sicians. We participated in the growth and improve-ment of intensive acute dialysis rescuing patients fromthe jaws of death.We participated in the developmentof chronic dialysis which in 1959 was 100% lethal,nowwith millions on dialysis, many after decades withoutrenal function.

But there was also the disappointment of seeingthe mortality in the first decade of chronic dialysis,brought down from 50% to 10% at 1 year, to starttripling over the last 25 years. It is a mind-numbingsimplification that one can reduce dialysis to a math-ematical equation “Kt/V,” the result of being mes-merized by a computer screen, without any thoughtsof the physiology. “The artificial kidney” is a machine

to simulate the physiology of the native kidneys, notthe amount of urea removal.

THE BEGINNING

In the fall of 1956, I started my first clinical rotationafter 2 years of preclinical medicine at the Universityof Lund, having read and memorized tons of facts ininnumerable books. This is different, very different,the first encounter with real patients. I think to mostof us who have gone through this, it is a scarymoment: I am not a real doctor, just a medicalstudent; will I miss important clues and signs? Am Iany good with the stethoscope?

I reported to the Department of Internal Medicineat the University Hospital. Professor Nils Alwall wasthe attending physician. It was now 10 years since hestarted his treatment with the artificial kidney in1946—the first complete dialysis apparatus, one withboth dialyzing and easily performed and measuredultrafiltration capacity. I was told that my patient wasin her room and I went in, very uneasy, uncomfort-ably feeling a bit of a sham in my white coat. In thebed was a young woman, semiconscious from preec-lampsia with acute rapidly progressive uremia,an almost 100% lethal complication, in her latepregnancy. She had been flown in from northernSweden by the Swedish Air Force to the only dialysisunit in Sweden. Taking the history of her disease wasvery brief—she was beyond telling anything. I lis-tened to her heart and lungs; they seemed fine, but Ihad no particular confidence in the accuracy of myphysical diagnosis. As I sat, not knowing what I wasnow supposed to do, the door opened, a couple ofnurses and technicians came in with a gurney and wewheeled her down to one of the two dialysis rooms. Ifelt a bit wobbly as one of the dialysis staff put in thetwo glass cannulae in her arm and connected them tothe Alwall dialysis apparatus, and a 5-h dialysisbegan. It took time to adjust to the sight of blood.When dialysis finished, the cannulae were bandagedand left in place with a heparin lock, and my firstclinical day came to an end. The next day, one coulddoi:10.1111/j.1525-1594.2012.01501.x

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elicit a few words from her. It was time for the nextdialysis. In the middle of the dialysis, she beganhaving cramps and quickly delivered a very vitalbaby girl. Now there was a lot more blood, almosteverywhere. A kind nurse escorted a white-facedyoung medical student to a chair. After four moredialyses in a 30-day period, urine output resumed andthe blood urea nitrogen rapidly normalized, she wassent back home with her baby, and in me the hookwas set—the marvel of the Alwall artificial kidneysaving two lives!

NILS ALWALL

No one has done more to promote dialysis thanNils Alwall, the son of a small farmer in southernSweden. He had a PhD in biochemistry and trained inpharmacology and in physiology in Hungary. In theearly 1940s, aged 36, he shifted his interest to clinicalmedicine and began a series of remarkable dialysisexperiments, using rabbits for his studies of pulmo-nary changes in uremia and their reversibility withultrafiltration with and without dialysis. He thendeveloped the first clinical dialysis apparatus withlarge and predictable ultrafiltration capacity. It waslight-years ahead of the simultaneously developedartificial kidneys in The Netherlands and in Canada, atriumph of considerations of renal physiology andthoughtful mechanical solutions. While others tink-ered with less perfect devices, Alwall promoted anddeveloped dialysis in Sweden and in the world. Hewas a founding father and president of the SwedishAssociation of Nephrology, the European Dialysisand Transplant Association (EDTA), and the Inter-national Society of Nephrology. By 1957, Alwall haddialyzed some 400 patients that then arrived at a rateof two per week, with over 1000 dialyses. I rememberhim returning from a dialysis meeting in the USAand somewhat wonderingly saying that he alone hadtreated more patients than all the other attendeestogether. There was a special drama; the desperatelyill patients, mostly the result of surgical complica-tions, were flown in from all over Sweden and alsofrom other countries. A special professorial chair, avery unusual event in Sweden—Professor of RenalDiseases—was created for him in 1957 and he wasgiven his own department of nephrology, probablythe first in the world. With that came several newpositions, one was a research assistantship and I wasthe first one to hold it. His nephrology department,with the world’s busiest dialysis unit, was an idealplace to train and physicians came from all over theworld. It was an enormously stimulating place to be,with world famous researchers in nephrology and a

multitude of ingenious young physicians who came tolearn and teach. In a “Festschrift” to Alwall in 1985,there were 64 contributing authors from every cornerof the world.

LEARNING CLINICAL RESEARCH ANDACUTE DIALYSIS

I worked with Alwall doing clinical research in thelargest acute renal failure program in the world from1957 to 1962. It was a true vortex for learning withspecialists in surgery, infectious diseases, and respira-tory physiology that were attached to the clinic andwith the extra stimulus from visitors from all over theworld. It was the first true intensive care department.The result of our analyses was published as Thera-peutic and Diagnostic Problems in Severe RenalFailure, edited by N. Alwall, Scandinavian UniversityBooks, Stockholm, 1963. It mapped the horrendouscomplications in over 1000 patients, most due tosurgery problems, and how to overcome the difficul-ties in diagnosing them and how to treat them. Thosepatients 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 verysick patients; none was denied access.

TO AMERICA—THE SCRIBNER SHUNT

In 1962, I received a scholarship to spend a year asan intern at Bethesda Lutheran Hospital in St. Paul,Minnesota. The last 3 months of the internship waselective and I went to Seattle and spent severalmonths at Belding Scribner’s dialysis unit learningthe technique of chronic dialysis, then into its secondyear of development. As an anecdote illustrating theexplosion in dialysis development, in 1959, a highschool classmate of mine was admitted to Alwall’sdepartment with acute renal failure from glome-rulonephritis. 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 theworld. Three years later, while at Scribner’s clinic, Imet Robin Eady, then in his second year of dialysisfor irreversible glomerulonephritis. He is still aliveover 50 years later! The hook was planted deeper. Iran an acute dialysis unit at the Bethesda hospitaluntil the end of 1964 and I worked with the renaltransplant team at the university participating in theirresearch.

BACK IN SWEDEN—THE RISE OFCHRONIC DIALYSIS

At the end of 1964, I returned to Sweden as anattending physician in Alwall’s department. The

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department trailblazed chronic dialysis in Swedenand it was very exciting to work there. The dialysistechnique was refined, the various problems in thechronic patients (anemia, neuropathy, and bonedisease) were analyzed, and therapeutic maneuversdeveloped. Disposable dialysis filters and safe auto-matic dialysis delivery systems were developed withthe newly founded Gambro Company and testedclinically. We, thus, with many other centers, partici-pated in clarifying the many new and unique meta-bolic problems of chronic dialysis and how to solvethem. These years were exciting discovery and trail-blazing years and they bore fruit.The first dialysis andtransplant registry by the EDTA in the early 1960sreported that the first-year dialysis mortality droppedfrom about 50% in the early 1960s to 10% 10 yearslater. The first US report of 302 chronic dialysispatients from 1969 reported a 12% first-yearmortality.

UNIVERSITY OF MINNESOTA:TRANSPLANTATION

In 1967, John Najarian succeeded Owen Wangen-steen as chair of surgery at the University Hospital inMinneapolis. Najarian came out of the trailblazingtransplant center at Moffat Hospital in San Franciscoand made it his main work to develop the smallMinnesota transplant program into a world-classoperation. This necessitated the development of aforceful dialysis unit—an absolute requirement for atransplant program. I applied for and got the newposition as chief of dialysis and moved to the Univer-sity of Minnesota hospital early in 1968.There was anexplosive growth in the dialysis unit, from a two-bedroom operation run by urology residents to asuperactive 10-bed unit accepting several patients aweek. The technique was developed quickly, resusci-tating the very ill patients, and improving them sothat they could withstand the many invasive diagnos-tic tests and operations necessary for their transplant.

There followed 13 years of intense researchresulting in approximately 300 articles. A specialsystem for hemodialysis of newborns and very smallchildren was developed. It consisted of a smallshunt, dialysis filters requiring only 15 mL to prime,weight monitoring during dialysis, accurate to within10 g, a formula to use precise blood and dialysateflows to avoid over- and underdialysis, and a systemusing mannitol to abolish any osmolality changesduring and between dialysis. This was a collabora-tive effort; Ted Buselmeier, my associate, andMichael Mauer, a pediatric nephrologist, wereimportant contributors.

For the first time, large-scale dialyses of patientswith diabetes were undertaken. It was regarded ascontraindicated due to the poor results of others. Theregulation of blood sugar in the functionally anephricdiabetic patients was refined, and intraperitonealinsulin in peritoneal dialysate was introduced in 1971and quantitated with addition of tracers. The work inboth acute renal failure and with dialysis of diabeticpatients was more enhanced by work with Eli Fried-man, who became the great proponent for treatingthe patients with diabetes as all other patients. Thedialysis of patients with diabetes became of world-wide interest. Rashad Barsoum with a whole teamcame from Egypt, Heitor Borges came from Brazil,Caesar Pru came from Venezuela, von Hartitzschcame from New Zealand, and Francisco Rodriguezcame from Spain, to mention a few.

Ted Buselmeier studied intrapericardial steroidinfusion in pericarditis and developed new arterio-venous shunts and improved the operative tech-nique for fistula formation. Ultrathin dialysismembranes and new disposable dialysis filters weredeveloped with the new dialysis equipment manu-facturers. Hemolysis problems from dialysate con-tamination were discovered and cured by ascorbicacid addition to the dialysate. Perhaps the mostimportant contribution was the formulation of theunphysiology hypothesis, that many of the seriouscomplications occurring in hemodialysis patients isnot so much caused by toxins but by the intermit-tency of the procedure that brings havoc to the inte-rior milieu. It was first formulated and studied in1973 and developed over the next 5 years. Its worthhas been well proven by the superior results ofquotidian hemodialysis now rapidly expanding.About half of the articles analyzed problems intransplantation—that effort mainly led by RichardL. Simmons, by far the best brain in the transplantcenter. Although not strictly being in the artificialorgans field, it resulted in remarkable improve-ments, trailing only those achieved in dialysis. In1964, when I first followed renal transplantation atthe University of Minnesota, then performed only inyoung patients with glomerulonephritis, the deathrate 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 CENTERAND ETHICAL PROBLEMS

In 1981, a new chief of medicine came to the Uni-versity Hospital. He was a nephrologist without anybackground in dialysis. He found clinical work of

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dialysis of no interest or importance. “When I makerounds in dialysis, I put on my roller-skates” was hisexplanation when withdrawing residents and stu-dents from learning dialysis. This peculiar disdain iswidespread in nephrologists who prefer antibodies topatients, screwy looking glomeruli to real faces, andhow potassium moves in the turtle to difficult elec-trolyte problems in the acutely ill. It is a continuousproblem that bedevils dialysis in the academic settingand, thus, in fellowship training. One of Alwall’s suc-cessors voiced her absolute uninterest in dialysis, “Iam not a washerwoman.” Of course, it is commonpractice by those who are mediocre, or not even that,to bad-mouth and downgrade excellence in others orridicule interest not in line with their own. I wouldnot work in such an atmosphere and moved to Hen-nepin County Medical Center in Minneapolis at theinvitation of Fred Shapiro and Alvin Schultz.

My main research there switched to empiricalanalyses of ethical problems in dialysis. I encounteredearly a number of patients at the chronic dialysis unitat Hennepin who decided to discontinue dialysis anddie, a problem not encountered in the relativelyyoung and healthy patients accepted for transplanta-tion at the University. It was until then an unde-scribed problem. By a review of all deaths in the unit,it was clear that halting dialysis was secondary only tocardiovascular disease as a cause of death in chronicdialysis patients. The first publication about haltingdialysis appeared in the New England Journal ofMedicine in January 1986 and resulted in a phoneddeath threat by the Army of God. They had a bulletwith my name on it they said. I advised them to makesure their first bullet hit properly as I had a number ofgold medals from the Swedish army attesting to myskill in hitting man-sized targets with all sorts of smallcaliber guns. I have never been shot at, and thus havenot had the opportunity mentioned by Churchill, thatone of the most exciting things one can experienceis to be shot at but missed. There followed over20 articles and two books addressing the problemof stopping treatment, since then recognizedeverywhere.The first publication met with two differ-ent responses in letters from physicians, criticism thatit was a terrible betrayal of the Hippocratic Oath, theother that it was a relief to bring this into the open forstudy, discussion, and improvement.

The second ethical problem I discovered when Ianalyzed acceptance rates to dialysis and transplan-tation and found clear evidence of rationing byage and gender in dialysis and also by race intransplantation.This was described, in 22 articles, twobooks, and well over 20 presentations between 1984and 2003. I got very severe criticism, bordering on

abuse, for this description of a less than perfect broth-erhood, but the problem—that still exists—has sincebeen described by many others around the world;young, rich, white men everywhere have preference.Letting skeletons out of cupboards raises eyebrowsand stokes anger.

KAROLINSKA INSTITUTE/UNIVERSITY OFALBERTA: THESIS OF ETHICAL PROBLEMS

In 1986, I moved back to Sweden as Chief of Neph-rology at the Karolinska Hospital in Stockholm. In1990, I moved to the University of Alberta in Canada.Most of the work was follow-up on large numbers ofdiabetic patients on hemodialysis, continuing theexamination of stopping dialysis, and following thesedying patients to try to improve their care and makeit more comfortable and less stressful to all. LewCohen from Massachusetts was an important stimu-lator of this in his USA-Canada-wide cooperativeresearch effort. I also continued to study the injusticein selection to dialysis in the USA, Canada, andSweden. Together, the studies and descriptions ofthese ethical problems in medicine culminated in myPhD thesis “Giving life—Giving death. Ethical prob-lems in high technology medicine” in 1988.

There were also analyses of vasoactive and stresshormone changes in dialysis, led by Ingegerd Odar-Cederlof.A very exciting interlude were the 4 monthsas visiting Professor of Nephrology at the Universityof Cairo, working with Dr. Rashad Barsoum mappingthe epidemiology of renal failure in rural and urbanEgypt. Diabetes was more common than Schisto-soma! About 150 articles were published between theyears 1986 and 1997.

THE FALL OF DIALYSIS

The development of the shunt in 1960 suddenlyopened the floodgates of chronic dialysis. All overthe world, people struggled to meet the demandboth by the number of patients and improving thesurvival that immediately filled every dialysismachine the moment it was installed. Businessleaped to the assistance and large companies wereestablished and grew into a billion-dollar industry.As people struggled to accommodate an endlessnumber of patients, one way was to shorten thedialysis time so a nurse and machine could treatmore patients. There then occurred an unfortunatemarriage of business interest and a single-mindedmathematical approach to dialysis, the Kt/V. Severalsmart mathematically oriented physicians, with littleor no physiological thought, simply stated that wecould just increase clearance and shorten dialysis



time and the patient will then receive the same doseof dialysis. A Kt/V of 1.2 was “adequate.” It was ofcourse honey to the ear of those who ran dialysis forprofit; time is money. So poor research without anyphysiological considerations and business consider-ations took the place of careful clinical research. Theregulation 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 ofthe slow movements of these substances in the bodyduring dialysis. As a consequence, dialysis time wassuccessively shortened from 12 h to 3 h thriceweekly, from 1970 to 1987. The first-year mortalityrose in proportion to the shortening and increased250% from 10% to around 24% and has thereremained. Meaningless bureaucratic attempts bywell-meaning committees and nephrology associa-tions focused on how to treat symptoms: give eryth-ropoietin for anemia, fill patients up with phosphatebinders, use antihypertensives to achieve an arbi-trary blood pressure. None addressed the realproblem; dialysis has become too short and toobrutal. You cannot remove a volume equal to allcirculating blood water in 3 h in 60–70-year-oldpatients without doing serious harm to them.Hypotension during dialysis has become a majorproblem dealt with by vasoactive substances or com-plicated sodium grading schemes. Witness the olddialysis patients after dialysis in Trendelenburg’sposition and either drinking salty broth or receivingintravenous saline in the dialysis waiting room.Absurdly, the fluid, too quickly removed, is nowpoured back in! As a result, we are left with anor-exic, malnourished, arthritic patients, hypertensivebetween and hypotensive during dialysis, and with adeath rate three times that in the 1970s, and that isworse than for most cancers.

AKSYS AND DAILY HEMODIALYSIS

In 1997, while on a sabbatical studying biostatisticsat Wake-Forest University in Winston-Salem, I wasinvited to be the medical director at a small companyin Lincolnshire, north of Chicago. Rod Kenleystarted the company with private money. He hadbeen very impressed by the results of daily hemodi-alysis of Umberto Buoncristiani. The company wasdeveloping a new hemodialysis machine, to be useddaily in the patients’ home, the PHD—personalhome hemodialysis. It incorporated ideas from the1970s by Umberto Buoncristiani, Perugia, Italy andparticularly solutions proposed by Zbylut Tward-owski, Krakow, Poland, and, later, the USA.

For me, it was a natural closing of a circle thathad begun 25 years earlier with my formulation ofthe unphysiology hypothesis. The PHD machinewould make the most physiologic dialysis, quotidianhemodialysis, a practical reality. I stayed with thecompany until retirement in 2006. Much of thework was to deal with the FDA to get the machineapproved, which was in 2002. Much of that creditgoes to three veteran clinicians, researchers, andtrailblazers in home hemodialysis: Chris Blagg atthe University of Washington in Seattle, ZbylutTwardowski at the University of Missouri in Colum-bia, and John Bower at the University of Mississippiin Birmingham.

The main effort of my research, that continues,was cooperative large analyses of quotidian hemo-dialysis, and, since 1997, another 80 articles havebeen published. Many dealt with quantitating quo-tidian hemodialysis, a careful international coopera-tive effort of quantitation of phosphorous andbeta-2 microglobulin dynamics in dialysis by collec-tion of all dialysate where Ingegerd Odar-Cederlofin Stockholm, Chris Blagg in Seattle, and Todd Ingin Chicago were important participants. My researchhas also involved the evaluation of factors associ-ated with survival in quotidian hemodialysis. Themost important leaders have been George Ting atMountain View, California, trailblazing short dailyhemodialysis during the day, and Robert Lockridgeat Lynchburg, Virginia, leading the effort of longnight home hemodialysis. They have been trueheroes in their effort to improve the dismal state ofdialysis, in the face of huge administrative, bureau-cratic, and political obstacles. Our most succinctfinding has been that dialysis, with a weekly stdKt/Vof 2.4, accepted as “adequate,” is grossly inadequate.In close to 200 patients followed up to 10 years onquotidian hemodialysis, there is a continuous sur-vival improvement at least up to a stdKt/V of over5.1, possible only with over 36 h dialysis per week.Long night dialysis has a survival rate four timesthat in age-, gender-, diagnosis-, and race-matchedpatients on thrice-weekly patients in the USA. Thesurvival of patients on short daily hemodialysis istwo times better.

*†‡Carl M. Kjellstrand MD, PhD, FACP, FRCP(C)*Clinical Professor of Medicine Loyola University,

Chicago, IL†Adjunct Professor, SUNY at Brooklyn,

New York, NY‡Docent, Karolinska Institute, Stockholm, Sweden

E-mail: [email protected]

PIONEER SERIES EDITORIAL 579


BIOSKETCH

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

He is an Adjunct Professor of Medicine at theState University of New York at Brooklyn and Clini-

cal Professor of Medicine at Loyola University,Chicago and Docent at the Karolinska Institute inStockholm. He is an honorary member of the Peru-vian Society of Pediatrics and Nephrology and theVenezuelan Society of Nephrology. He is a fellow ofthe American College of Physicians and the RoyalCollege of Physicians and Surgeons, Canada andis a life member of the Asian Pacific Society ofNephrology. He has been invited as a visitingprofessor/lecturer at over 400 national and interna-tional meetings and academic institutions.



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