|Online Slide/Audio Symposium|
Nordic Nephrology Days |
University of Lund, May, 1997.
History of Dialysis. Men and Ideas
Part Two 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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AnticoagulationSo with that we have followed through the membranes and back here at the turn of the century, people really understood urea, molecular weights, transport, and so forth. Let's then go over to anticoagulation. There are no real men in anticoagulation, early on at least. It is folklore, this discovery.
This is an Amazon giant leech having its breakfast on this slightly skeletal man here. Obviously people long ago discovered that when you rip the leech off the body, you bleed like crazy afterwards. The leech does something to you that thins the blood so that it doesn't clot. And there is no discoverer of that. It just comes from folklore. As you know, leeches have been used for thousands of years for all kinds of medicinal purposes.
Why leeches need hirudin
Now what the leech does when he leeches on to you is he leeches to the skin... he has three very sharp teeth, he gnaws a hole, and then he sticks very carefully this long needle right into your vein. Out here he secretes hirudin that thins the blood. Then he has breakfast and the blood doesn't clot, and the leech is really happy and you are not.
Use of hirudin by Abel and Roundtree
Now I would like to jump: The first treatment known with an artificial kidney led by Abel and Roundtree, all of you know, about 1913. About 1/3 of that article is actually devoted to the description of how to prepare hirudin.
They complained, "We bought hirudin at an enormous price of $27!". And they used half a gram. Imagine, $14! And they said, "That is too much." But they said, "We have discovered that you can buy leeches by the thousands from France for $20, then we can make 10 and 15 and 20 grams. We'll save a lot of money." They go on to describe how you do that. The way you do it is to grab the leech with the forceps, about the 7th ring from the head, they cut off the head. And you do that with thousands of leeches into the bottle. Then you grind it up with sand, put water on it, filter it, and the filtrate contains hirudin, which you can then anticoagulate with.
As a by-line, you know that hirudin is coming back as a biogenetic substance these because it has some very good properties, but it did not at that time because of its impurities, as I will describe to you.
|Actually the leech industry became a big deal, and there are some grisly images; for example, in France they drove old horses into leech ponds to feed the leeches so that they could send them to the like of Abel and Roundtree.|
Discovery of heparin
It is an impractical substance to use. The real anticoagulation, heparin, came in 1916. There is a sad story behind heparin.
|Jay McLean, a young medical student from Boston came to John Hopkins Hospital in Baltimore in the summer of 1915 to do research. He was asked to take dog's livers, grind them up, and extract out of them a substance that promoted clotting.|
You'll remember that was when surgery took off, people bled, and the surgeons wanted something to dab on to stop the bleeding. So Jay McLean started going and extracted all kinds of things out of these livers.
|But he said, "I found something opposite to what I was set to do. I found a substance here that will markedly inhibit the coagulation. Isn't that interesting? I'm going to study it."|
That was the last we hear of Jay McLean.
|Two years later, two professors from Johns Hopkins, Howell and Holt, publish "Two new factors in blood coagulation: heparin and pro-antithrombin", where they rediscover Jay McLean's story here.|
What happened here? Who was Jay McLean? A student publishing without his professor. Who were the professors who stole his idea? We'll never know. I once gave this to a cardiologist who had been the editor of the very famous journal, Circulation. He said, "I know Jay McLean. I'm going to call him. He is still a physician in Florida."
|So Jay McLean was asked to write the story of the discovery of heparin. He begins then telling how he was a premedical school student, he needed money, he went to work, and he made this discovery. Then he dropped dead. Boom, like this. He developed a malignant lymphoma and was dead in a couple of weeks. So what happened in the story we will never know.|
But for you who are young, don't trust the professors too much, I guess, is the general advice one can get from the story of men and ideas here.
|From that point on, anyhow, the first use that we know of heparin was done by Charles Best of insulin fame at the University of Toronto to treat a case of pulmonary embolism.|
An anticoagulant was now available
With that, as you can see, we have come here to the mid-30s. Hirudin has been replaced by heparin. It has been purified, and the Swedish industry did much of that. There is commercial availability.
Putting the pieces together: Abel and Roundtree
With that we come over to the very, very first dialysis known by Abel, Roundtree, and Turner. In 1913, they published on the removal of diffusible substances from the circulation blood in living animals by dialysis. You can see the introduction, the method, the apparatus, that I will show to you, the technique of the experiments, and you can see the preparation of the leech extract taking up three full pages in their article here. So that was published in 1913 -- 84 years ago in December.
The Abel and Roundtree dialyzer
Their device is here, and you have all seen it. I marvel at how the hell could they do it. I have no patience at all. If I work at something mechanical for five minutes, I jump on it and destroy it. Obviously I would not be able to construct this here. But what it is, these are collodion membrane tubes. The way they were made by Abel and Roundtree was to take cotton, solve in the nitric acid so they get a gelatinous solution; they then put a glass tube, put the solution into it and twirl the tube around -- that's how they describe it -- cover the whole inside of it, continue to twirl it to get an even coating, and let it cure for several days. Then they took the glass tube, heated it up so it enlarged, put a finger in and slide the whole fragile tube of celloidin out of it. Each of these tubes were hand-made that way.
Then they had the glassblower make this complicated hollow-fiber arrangement here. How they tightened it in both ends I fail to understand. Then it was put together in this apparatus. Dogs were given leech extract, the blood flowed in here, branched out, ran through this tube, collected back here, returned. And on the outside, they ran dialysate solution.
They did all kinds of studies of urea, creatinine, uric acid, blood glucose and so forth. Abel then toured Europe for quite some time and talked about this device, showed it, and had great plans in using it for patients with uremia. What happened was the First World War came. Basically at that point all future research disappears. As you look through the old literature, there is none there.
But the War came to an end. In 1926 someone, 13 years later, picked up the idea, and it's George Haas in Germany.
The Haas dialyzer
He had a device exactly like the one made by Abel and Roundtree. Each of these here contains collodion, two collodion tubes joined with a U tube here. Blood comes from the patient, is pumped by blood pumps through a clot filter and then it flows back and forth through these many tubes here. Then it returns to another clot pad and back to the patient. The patient was anticoagulated with hirudin.
Here are the case reports of what Haas did. Here is a 53 kg, very anemic, cachectic uremic who throws up everyday. The blood indikan level was very, very high. The BUN is not all that high -- under 50 mg per deciliter here. He throws up daily. At 6 o'clock in the morning -- he was an early riser -- the patient was given one gram of "jodkali" (potassium iodide) and Haas used that because it was easy to determine chemically. Then he measured how much iodine there was in the urine during the next half an hour, and it was half a milligram. Then at 11 o'clock, the patient was given a hirudin solution, and the blood ran from the radial artery and they continued to dialyze the patient for 35 minutes here. He removed during that time 10 mg of iodine. In other words, the machine was at least 20 times more efficient than the diseased kidneys were.
Hirudin side effects cause abandonment of Haas' attempts at dialysis
Then things started to go bad. The patients threw up, had headache and went into shock. Over and over again the patients got ill, they spiked a temperature, they had headaches, they had chills and fevers and the temperature went up here. And I bet that the reason was the impure hirudin solution that they used. Had he read McLean's article and used heparin, Haas would have been the first to have a successful artificial kidney. But after five or six experiments, Haas gave up. He simply couldn't do it because the technology wasn't quite there.
|Another ingenious person, at the same time fooling around with an artificial kidney was Heinrich Necheles. He was a physician from Lettonia [Latvia], I believe, and he ended up to be a professor in physiology at Peking University. So he has a career that Dr. Klinkmann has partially followed here. And he presented his method for dialysis in 1926, the same time as Haas did here.|
And his was perhaps even more ingenious because he took peritoneal membranes from calfs used by Chinese goldsmiths to beat out gold into very thin layers and overlay things. He folded them up into envelopes, tightened up the ends and then ran dog's blood with hirudin through these membranes and could also show that he could remove urea.
|And if you don't believe me, read the summary yourself. It's available in your library.|
|Here is Dr. Necheles himself. Dr. Necheles actually visited Dr. Alwall's clinic back in the '50s. I remember seeing him as an old man, but I didn't know all of his achievements at that particular time.|
The combining of the three areas of knowledge
So everything is set to go here in the mid-1930s. The three areas of knowledge have been fulfilled. The early pioneers have fooled around here.
|And indeed in 1937, William Thalhimer marries all the techniques.|
He takes a dog, removes both kidneys, watches the urea go up, gives the dog heparin, attaches the femoral artery...femoral vein through a long cellophane tube that he has in a water bath and is able to lower the nitrogen. He describes this in 1937 in this particular paper here. Here he says that we show it can be done and now we know that there are certain conditions where you need temporary support and an artificial kidney -- this is the way to go, and we will do it. And he will work with whom? Dr. Charles Best shows up here again as one of his coworkers!
And then what happens? The next day, the Führer moves into Berlin and all research in the artificial kidney stops.
Effect of World War II on medical science
I think it is very dramatically illustrated. You can see here in Die Berichte Über Wissenchaftliche Biologie, that in 1943, the first volume is there. Then they combined 1943 and 1944. There is no volume in 1945, '46, or '47 here.
And with that I have but two minutes to go to fulfill my task to set the stage for Dr. Klinkmann to give you the development from that point on. Thank you very much for your attention.
Now, some people ask me, "Why did I do this?" This takes time to go to the library. Particularly technologist physicians ask that.
[Implied in that question is the erroneous conclusion that only technological studies are worthwile. First, today's technological revolutions are tomorrow's cartoons and waste paper basket fillings, while historical contemplation gives rise to endless new ideas. Haas failed because of the use of hirudin. Today hirudin is reborn. While it is tedious to plow through the boring prose of technical writing it is great fun to trace down discoveries through centuries.]
What can I do better than to quote Nils Ferlin's [hilarious poem "Truthfully" in his collection] Kejsaren's Papegoja (The Emperor's Parrot):
I was among those
who one night in May, 1814,
and threw Voltaire's bones
on the dump
by Barrière de la Gare.
I didn't do that for the sake of the Church
or for the sake of France,
I only did it because I thought
it was damned good fun!
Thank you very much.
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