|Online Slide/Audio Symposium|
Nordic Nephrology Days |
University of Lund, May, 1997.
History of Dialysis. Men and Ideas
Part One of Two
Dr. Carl Magnus Kjellstrand
Dr. Kjellstrand is currently Medical Director of Aksys, Ltd., and is Visiting Professor of Medicine at the Loyola University Stritch School of Medicine in Chicago.
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Dr. Jonas Bergström:
The next speaker is Professor Carl Magnus Kjellstrand. I don't think he needs a particular introduction. He is very well known to all of you. I just want to point out that he is an original pupil of Nils Alwall. He belongs to the "golden" generation. Many of those who were educated with Nils at that time became very famous, very prominent, among them Carl Kjellstrand. He spent most of his time in later years in the United States, and his latest academic position was Professor of Medicine in Edmonton, Alberta. I think that Nils Alwall would have been very pleased to have you as a lecturer at this symposium, and I can think of no one who is better suited than you to lecture about the history of dialysis, "Men and Ideas". Please.
Tribute to Dr. Alwall
Thank you very much, Jonas, Professor Bergström, Professor Rippe. You have really pleased and made me proud with the invitation to come and speak at the university where I trained with one of the outstanding people in Swedish medicine. It is a particular honor to speak here today because Mrs. Alwall and her daughter Nethan are here and have honored us with their presence. Thank you very much for coming to us here.
The first patient dialyzed in Sweden by Dr. Alwall
We are here today to honor Professor Nils Alwall, who 50 and 1/2 years ago performed the first dialysis in Sweden. This is a case--a 39-year old man with glomerulonephritis came to the University of Lund (for treatment using) the ideas had materialized in the ingenious machine that was the Alwall kidney. As you can see, the patient was extremely ill with urea, serum nitrogen that rose from 3 up to 400 mg/dL; he was treated once with a fall in the urea level. He died a few days later of pneumonia.
Growth in dialysis patients has been worldwide
Since that time there has been an enormous development of dialysis. From a handful of patients, there is close to one million patients on dialysis today. That is an astounding number. For example, in Japan, which has the highest number of patients on dialysis because there is no transplantation taking place there, one in 800 Japanese today is alive on chronic dialysis -- It stuns me -- one in 1,000 in the United States (the second highest population rate today on dialysis); in Europe, about 1 in 4,000; and in the rest of the world, because dialysis is reasonably expensive (although compared to weapons trade the cost is peanuts) about 1 in 30,000 patients. This is a fantastic development, and I don't think the story has been told loudly enough.
Nils Alwall and those who came before
We are here to celebrate a man and his idea. But when I look at science, I look at it as a big house that all of us build together. Every one of us who worked in research and clinical work contributes bricks that build this house. Now if some people, like Nils Alwall, are lucky enough to be at the right time, at the right moment when things are ripe and because of an ingeniousness can collect the data -- they would put in the cornerstones and porticoes to make them famous, then most of us have to serve as humble bricklayers.
|But we should remember, also, that Isaac Newton said, "If I have seen farther, it is because I've stood on the shoulder of giants."|
How Dr. Klinkmann and I divided up the subject matter
When Dr. Klinkmann and I were asked to do this task, we did the senility test. Horst said, "Do you remember what you ate yesterday?" I said, "No." "A week ago?" And I said, "No." And it showed that I had forgotten what had happened the last three months, and Dr. Klinkmann had only forgotten the last month. So we decided I should speak of the very old stuff, which is (the history of dialysis) up to Nils Alwall; and Dr. Klinkmann would then begin because he has a much better memory than I do.
The foundations on which Dr. Alwall built
So my task is then to say: What was it then that enabled Nils Alwall here, 50 years ago, to do the first dialysis? And then there is the simple consideration: What was needed in understanding for him to put things together?
The three crucial elements needed for dialysis to be possible
This is an old Baxter slide, "What happens during dialysis?" Blood runs through the semipermeable membrane. You have to anticoagulate because it clots. You have to know what to take out and what to leave behind and what to put back in again. You have to understand uremia and its metabolic abnormalities. And you have to have a very reliable membrane that doesn't rupture and that performs and is strong and defined in its character, and reproducible from time to time.
|Anticoagulation, semipermeable membrane, know what to remove and how much. Then let's go through the development of these things, and randomly we will begin with membranes.|
MembranesSmokeless gunpowder, cellulose and nitric acid
No membrane was made to be a membrane. All membrane technology is a spin-off of military technology. Because right back here in the middle 18th Century, black powder was still how you killed your neighbors when you didn't like them really much. Black powder is a clumsy thing, because if it gets wet, it doesn't fire; and when it fires, it smokes; and if you don't hit (your enemy), he can see where the smoke is, and he can hit you back again. You don't want that. So the invention of smokeless powder: solve cotton in nitric acid, nitrocellulose, nitroglycerine. As a spin-off of that, Plouzé, who was busy with it, discovered that balancing the amount of cotton and nitric acid, you can either get a solution that exploded or a solution that made a very strong membrane, and we'll come back to that.
The next thing here is about 150 years ago, when the first dialysis experiments were done in Glasgow, and this is Thomas Graham, who is always shown at dialysis lectures because he is the discoverer, the inventor if dialysis.
Experiment of Dr. Graham
A simple experiment. He went down to the local pub, and a good bottle of beer with his friends, took the beer bottle with him home, cut it in half, and covered the bottom with pergamon paper. He lowered that bottle into a water solution and introduced a variety of solutions into the bottle and studied how quickly they moved from inside the bottle, through the membrane, and out.
And then he very carefully graded it. He used sodium chloride as one, as a standard solution, and then he added starch, sugar, alcohol, glycerine, and he could show that many substances, most of them, moved much slower than sodium chloride; gum arabic, for example, moved only 1/4000 as fast. He then said there exist molecules in nature that are very big (colloids) and very small (crystalloids), and they can be separated by a membrane. That was the very first discovery.
Membranes, war, and billiard balls
Now his membrane was not very practical. But, as I told you before, fooling around, making smokeless powder that shot straight, didn't smoke, killed your neighbor before he had the chance to see you, Plouzé then was able to make a very strong solution, collodion, but using less nitric acid and more cotton. Parks in turn added camphor to that to make billiard balls, which were getting in scarce supply at that particular time. That was finally even bettered by Hyatt.
|So in other words, membranes were not made to be membranes for dialysis--they were made to kill your neighbor.|
|Secondly, membranes became very useful during the First World War because a collodion solution is extremely strong. So when you made your rickety little airplanes, you covered them with collodion solution and they became very strong, and you could fly around and do all kinds of mayhem with them. One problem, an incidental bullet going through lit it up, and they burned like wildfire. Some of you who are as old as I am, not many, remember that one pleasure as a child was to set fire to photographic film, a virtually "whoom!", and that happened to the airplanes. Naturally, the pilots became very nervous about that and didn't really want to fight. When they saw each other, they kind of turned tail and went others.|
Cellulose acetate and billiard balls
That was not so good. At that time, somebody invented, that if you solve in acetate instead, it didn't burn and was equally strong. So there you have both the cellulose nitrous membrane cellophane and the cellulose acetate. All are a spin-off of military technology.
|And then third, it was stimulated by the fact that the elephants were being poached to death in Africa. The billiard balls became very, very expensive. They were made of ivory in those days.|
People couldn't afford to play their billiard until Hyatt discovered that collodion and camphor together made a very strong plastic. I'm told that billiard balls when you hit them very hard exploded and killed you, as they came right out of military technology. I don't know if it is true, but I've heard that. It makes for a good story.
Polymerization of cellulose
Now, all this was done in people's basements -- fooling around mixing, doing things, exploding, scaring their wives, and getting fingers blown off and so forth, until Helmut Staldiger, a German chemist, discovered that what you do when you solve cotton and let it cure, is, you rearrange the molecules; he introduced the polymer. He received the Nobel Prize for that in 1957.
Cellophane and the packaging industry
The next thing that happened was that the packaging industry got hold of these membranes and then they started to make cellophane in miles quantities, tons of them, and it is a useful package when you buy flowers today. They are using the membranes, for example. Sausage is still encased in them here.
Everything was ready. There was a membrane then that had been made. We knew it could dialyze, and it was ready for commercial application in 1935.
A basic understanding of uremiaUrea is isolated from the urine
The second then is about uremia and urea. Perhaps one starting point is 1773--220 years ago, when Hillaire Nurepuel did an experiment. Every single you one of you here can do this tonight. Go home, turn on your oven, pee in a pot, put it on the oven, let it boil away, and there will be a white substance (and an angry spouse). The white substance there is urea--the main excretory substance that we need to pee out as we eat the protein today. That's what Hillaire Nurepuel did. He said: There is something in urine that comes out of the body. It's a poison. He called it urea after urine, and we use the word uremia. He was said to be a somewhat senile lecturer, like me, that when he talked he used to walk out of the audience. He was a fascinating speaker. His pupils followed him to listen to what he said. I will not do that experiment with you here today.
Urea is synthesized
Now the next breakthrough here came in 1828 -- 170 years ago, when this man, a kind man, a German chemist, Wöhler synthesized urea and describes its molecular structure. Wöhler trained with a great Swedish chemist, Berzelius, the describer of the periodic system.
He went back to Germany. He was obviously a very kind man because all of his pupils continued their correspondence with him forever. In 1828, Wöhler did something that up until that moment had been absolutely undoable. Up until that point, there was a philosophical school that said two substances in nature, inorganic -- without life, organic -- with life. Only God can make the organic life-containing substances. Wöhler overnight killed that philosophical school by taking ammonia, carbon dioxide, and combining them -- two inorganic substances -- into urea, an organic substance.
|And describing it here. This was the original work that I found at the University of Minnesota in Annalen der Physik where Wöhler published his discovery.|
The importance of the kidneys and urine has long been
Where exactly people started to understand that the kidneys have something to do with uremia and with urine, I do not know because it is lost into the mist of history. This anatomic drawing is 3,000 years old and it's from Tibet, made by a Chinese physician. The Chinese had a very careful death statistics register thousands of years ago. Clearly it shows the kidneys in the right place. It looks like it is polycystic kidney disease that this particular person has. But it certainly is a very, very careful rendering here.
Perhaps one should mention in here is Claude Bernard. Claude Bernard was the one who defined that the kidneys don't have simply the role of excreting poisons but regulating our interior milieu. He was unhappily married to a wife who was constantly complaining that he didn't make enough money, but he made what is more important we think; fame instead.
By the 19th century, uremia is fairly well understood
From that point on, the knowledge literally explodes. If you look at uremia at the end of the 19th Century, this lecture very well describes the acidosis of uremia, the creatinemia, the phosphate elevation, and so forth. This is simply a lecture like the one I am giving here to you today, given 100 years ago in London.
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