Introducing Creatinine Clearance to Estimate Kidney Function
ASN Podcast
Published July 30, 2026 * 00:31:54
ASN CEO and EVP Tod Ibrahim hosts a discussion with authors Tobias Wang, Henrik Knudsen, and Henrik Dimke about their JASN article on how Poul Brandt Rehberg's discovery of creatinine clearance 100 years ago shaped GFR measurement.
Please note that this transcript was automatically generated and may contain inaccuracies. It is intended for informational purposes only. Refer to the audio for full context.
----Speaker 1: is of course enormous value. And I think any listener to this podcast will have experienced the awe of the eyes and the students when you tell them that the kidneys in that lecture you have just given has filtered the blood volume at least a couple of times.
Speaker 2: Welcome to Convergence, an historical assessment of kidney diseases, nephrology and health policy in the United States. I'm your host, Todd Ibrahim, Chief Executive Officer and Executive Vice President of ASN. So earlier this year, the Journal of the American Society of Nephrology published an editorial, and the editorial was entitled, The Introduction of Creatinine Clearance to Estimate Kidney Function, A Centennial Anniversary. And I'm joined by the authors of that editorial, and I'd like each of them to introduce themselves. Henrik, Dimke, starting with you.
Speaker 3: Okay, thank you very much for this invitation to tell part of this history. And my name is Henrik Dimke. I'm a professor at the University of Southern Denmark. I'm a professor on translational kidney physiology. So actually I'm a molecular biologist, but I worked in physiology for quite a long time now. And I'm particularly interested in the epithelial mineral transport and would focus on kidneys. So we look a lot on how calcium and magnesium is transported both via paracellular and transcellular routes in the kidney and use primarily transgenic animal models and physiological evaluations to look at this. And also I teach a substantial amount of medical students with respect to kidney physiology.
Speaker 2: Thank you. And one of your two co-authors, Henrik Neusen, could you please introduce yourself?
Speaker 4: Yeah, thank you. I'm probably the odd man out here because I am a historian of science. I'm currently working with the Danish National Archive, an archivist, but I'm also the author of a full scientific biography of Paul Pandeweber, some fish. 15 years ago. It came out in 2010.
Speaker 2: Thank you. And our final panelist for today's discussion, Tobias Wang, if you could just introduce yourself very quickly.
Speaker 1: Yeah, my name is Tobias Wang, and I'm a comparative physiologist, so I study animals. I'm a biologist by training, but teach human physiology and have an interest in the history of physiological sciences. And then I'm the editor of Apte Physlogic.
Speaker 2: So we thought we would tell this story chronologically. And so maybe we start at the beginning. So who would like to go first in terms of why you were interested in telling this story and publishing the editorial in Jason?
Speaker 3: I could maybe just say a few words first on what actually started this or why we were driven to put this story forward. I mean, if you look at it over the course of nephrology and kidney physiology, this is actually a relatively very important finding, which has very big implications for how the kidney or the understanding of how the kidney functions. every nephrologist and physiologist knows the glomerular phenthration rate, they know the creatinine, and they know these concepts, but they don't really know probably that much of this early work stems from Paul Brend Reber. And I think this surprised me a lot also that even in Denmark, a lot of people don't know about these contributions. So I think that this is rather interesting. And then this centennial was approaching and I think many of us was really interested in to put this out on the map and try to explain what happened because it's a super interesting story. So that was mainly, at least for me, one of the driving forces for this.
Speaker 2: So Hendrik is a historian. I'm just curious as to why this story isn't. better known? Why do you think it's been not sort of carried on in history in terms of our understanding?
Speaker 4: That's a good question. I think in Denmark, the history of physiology is a small field of interest. And that's when I started writing the book, I just felt awfully alone. But then I discovered literature on the history of nephrology and the history of, yeah. I think my main interest in Paul Ponfreber was as a politician of science. He was very instrumental in creating the research councils in Denmark, and he had a dramatic history during the Second World War when he went into the resistance movement. So he came out of the war as a central person in Danish history for some years, and he ended up being the chairman of biggest Danish science foundation at the time, the Carlsberg Foundation, and the chairman of the Danish Atomic Energy Commission. So it was mainly those things I was interested in. And then I also looked into his science. And afterwards, people came to me and said, you know, people working as doctors and doing science, physiological science. And people said, hey, that's very interesting. We didn't know anything about our our field. And so I got the opportunity to collaborate with a lot of interesting people afterwards.
Speaker 2: So Tobias, maybe this is the moment to introduce August Crowe, did I pronounce his last name correctly or close to correctly, to this story. If we go back to the 1920s, why is he so important to this story and to Rebert's career?
Speaker 1: Yeah, while I agree with him like that physiology is a small field, it's still a very big field in Denmark. in terms of all of our sciences, physiology is a quite sort of large discipline and Denmark publishers or daily scientists publish quite a lot compared to many other countries. And I think that is by and large due to our call. So our call was a biologist by training and we often say that he founded the field of so physiology. So zoology and physiology merged together, which is the field that I'm a professor of. But he comes out of a very strong tradition of physiology with his mentor Christian Bohr, who was nominated for the Nobel Prize several times for his oxygen secretion theory, which turned out to be wrong. And it was August Cole who demonstrated unequivocally that the theory was wrong. But August Cole had basically created a very, very active field of physiology in Denmark, starting out as a primarily respiratory physiologist, but then had started to move into the question of fluid balance of salt movements in and out of animals. So you could say that the intellectual environment was very ready when Rupert started with Albert Crow as a young student.
Speaker 2: And I should say that Crow did win the Nobel Prize in 1920 for his work. And I love in the editorial this quote that I'm just going to read and then I'll throw it over to Henrik Dimke and you to talk about the next steps in our story. But I guess when Robert approached Crow about his interest in working with the kidney, Crow's response was, yes, go ahead and take it on. I think it's a devilish organ and I've always steered clear of it. I do not want to have anything to do with it, but try to take it on. So that's sort of That's where the story starts, I guess. So if you don't mind, if the two of you could just sort of walk us through what happened at that moment?
Speaker 3: Well, I could say that Rabbi was in Cole's lab and he was actually interested in the capillaries. He thought the kidney was interesting because it had two sets of capillaries. And he thought that was a good basis for trying to understand the kidney, even though Cole tried to stay clear of it. So that is actually, I think, how it started. He really wanted to understand how filtration happened. But I think maybe also to take it just back one notch is that when he started, that had been a very long controversy, maybe stretching, I guess, 80 years or something, about how did the kidney really function. And I think you could see it in three steps. I mean, there were the ones that thought initially that it was just a secretory gland, basically. And then there came proposals from different people basically on that either the kidney could function by secreting solutes and other things and filtration probably was not so relevant or the other way around that there was a high filtration and then the tubular cells could modulate the transport. And I think that is basically what Reiber steps into when he's standing there. And what he decides is that he wants to try to measure how much the kidney actually filters. So he kind of moves it that step forward.
Speaker 1: I think for me at least, part of the important background there is that people had been looking at different animals and the ideas of going from anatomy to function started all the way back from Bowman's descriptions of Bowman's capsule where he looked at all sorts of different animals and where Karl Ludwig then continues with the idea and says that it must be filtration. And then nobody can fathom the amount of filtration that has to take place. And that's what has started in the start of the 20th century is that calculations on how much volume need to be filtered to account for what is in the urine comes up with these preposterous values of started out with 60 liters a day and now we know it's 180. But it's of course enormous values. And I think any listener to this podcast will have experienced the awe of the eyes and the students when you tell them that the kidneys in that lecture you have just given has filtered the blood volume at least a couple of times. So it of course was values that were unbelievable and therefore important to start to measure them.
Speaker 2: And Henrik, I'm just curious if I want to give you an opportunity from a historical perspective to contribute to this part of the discussion.
Speaker 4: Yeah, when discussing the kidney at this point of time in history, you have to think that, I have to acknowledge that the kidney is about, what goes on there is active and selective transport, both ways, both in and out of the tubular cells. It's a theoretical nightmare at this time. And I think that's what behind corpse when he calls it a diabolical organ. And you have to remember that at this point in time, you had not a very clear concept of active transport, what that was. So there was no clear understanding of that mechanism. And so people who was in sort of in a very mechanistic mode of thinking in physiology would label much of this as vitalism.
Speaker 2: I guess the not unfamiliar experience for many of our listeners is submitting a manuscript and not having it accepted for publication. So Henry, can you just walk us through, Tobias had made the point that the just the data were kind of unbelievable. So what happened when Rehberg first tried to publish his findings?
Speaker 3: Yeah. so basically Rehberg, he was already, I mean, he reasoned that he could use creatinine as a marker of filtration because it would be basically treated like a marker or a substance which would not be reabsorbed or secreted and not be affected. in any way. Therefore, he wanted to calculate basically how much was the filtration. And he did that already because there was some published values on creatinine. And then he sent it into a journal and basically he was told it was not good enough because this was based on some public, how to say, already published values and so forth. But he was already at that time calculating some pretty big numbers with respect to what at that time was thought would be a high filtration rate. So those numbers were actually turning out close to what he measured on himself later, but his manuscript was essentially rejected for negative of original data. And then he basically turned to himself as a test subject and tried to measure the clearance.
Speaker 2: And Tobias, I'm just sort of curious as to your reaction to the process, what he did, and then we'll talk a little bit about the findings.
Speaker 1: I think that the process of, he basically said that animal experiments were not going to be suitable, and therefore he then starts making measurements on himself by drawing blood and collecting urine, which actually wasn't all that uncommon for physiologists up until, let's say, the 1950s or 60s even. That was way before we had all these regulations, and I guess physiologists were a little bit more tough as they are today. So he basically performs these measurements on himself, which has a strong tradition in Cole's laboratory. Cole also did that. Many of the papers you can see values from Cole. So I think it was not all that uncommon at the time, in fact, but I still think it's quite heroic and impressive.
Speaker 2: Yeah. So he publishes his dissertation in 1926, studies on kidney function. And in your editorial, you describe it as a landmark collection. Just help us understand why it was such a landmark collection. Maybe, Tobias, we'll start with you and then go to our other two guests.
Speaker 1: What he does is that he basically assumes or makes the assumption that a substance that is filtered freely and which is not neither reabsorbed nor secreted will be a good measure for the glomerular filtration rate with the equations that had already been set up at the time and are based on Adolph Fick's principle of blood flow. But so what Reiber says is that he can look at substances and then he can see which of those substances secreted in the urine comes out with the highest filtration rate. And then he says that must be a minimum value for the glomerular filtration rate. And then he ends up with this calculation of the 180 liters per day. So it's a very logical argument, but the issue is, of course, that he dismisses that there is a secretion, which continued to be a controversial issue. So he theoretically says that there is no secretion. He actually has no evidence for that. So I think in hindsight, one could say that it becomes a seminal paper because he's correct in his assumptions But had he been wrong, and which he was later criticized for by Homer Smith, that there is some secretion, then he would have been off on his values. And then we would probably just have forgotten about the paper.
Speaker 2: So, Henrik, anything to add to that outline?
Speaker 4: Yeah, I think what the measuring the GFI is the first step for paper. The next step was to look at What goes on in the tubuli once you know how big the filtration rate is? comes into the tubuli, he was able to look at reabsorption mechanisms. And he showed very clearly that when you look at chlorine, you have a response when the plasma levels fall below a certain threshold, the body would re-uptake chlorine from the tubuli. Whereas if you have urea, the mechanisms of urea take back is more or less passive diffusion. So he viewed that as his also as a tribute to the field and to the understanding of Randall function. His interest was very much theoretical at this point. He wanted to contribute and solve some problems that was put forward earlier on in the field, mainly in Cusney's theory of Randall function. And I think he succeeded in that in giving more nuanced picture of also of reabsorption in the two.
Speaker 2: And Henrik Dimke, before we move on from this part of the story, I'm curious as to your reaction. I'm also really struck by this idea that he made assumptions that he couldn't prove necessarily, but because they were proven correct, it became seminal. I mean, it's a really interesting concept. I know it's not, it's common in medicine. I mean, I recognize this is more art than science at this point.
Speaker 3: I mean, he used creatinine as the clearance marker. And I think as we use it today, it's a very good clearance marker, but it is not the perfect clearance marker because it has a bit of tubular secretion that kind of can overestimate, of course, the clearance. I think what he really did was that he started doing these self-experiments. He ingested creatinine to increase the amount in the blood. Blood concentrations are not super high. So he was able to measure it and he could also measure it in the urine. He applied these clearance equations to really measure it and he came to these very high values of, to be as mentioned, 180 liters or 125 milliliters in that range, something between 80 and 200. It was very precise in that sense. And I think Haydn, who had worked on a little bit, been pro this secretory theory earlier, he also had made some calculations based on urea and he came up with a value of around was it 70 milliliters per minute. So and there he actually rejected the theory and said this is simply this is too much. This cannot be that there's so high filtration. So he really became even stronger speaker for this theory. But I think what Reiber is really showing here is that actually the kidney is functioning in this certain way by filtering a high load and then selectively reabsorbing certain things. And he shows this very well here, which no one has done ever before. So for me, I see it also as quite a big leap somehow. I mean, it's an unsettled debate that has been going on for some 80 years, but then now at least it moves towards some better closure. And I should also say that this is coming just immediately before this is happening, of course, You also have this publication on micropuncture that shows that there's a plasma-free filtrate that formed in these frogs when you puncture it by. So that it all fits very well together in this period. But again, remember, it's a very long, time, a time ago that this happened. So this was Newton Richards' bindings on.
Speaker 2: It's interesting too, because if I just took a step back and think from a very sort of US-centric historical context, 2026 is the 250th anniversary of the United States, and we're talking 100 years, so 150 years in 1926. You're saying this debate went on 80 years before that. So it's almost the entire history of this country. I just think it's important for people to take a step back and just think about the time frame we're in and I just find that really remarkable. Henrik, it sounded like you wanted to add something to what your colleague just said.
Speaker 4: Yeah, because Henrik mentioned he Newton Richards' micropuncture technique. Much of this is much of what goes on here is also about research techniques and adding precision, for instance, in micro situation. A Bass thesis was 5. separate articles and the three of them was about titration and measuring, how to measure these blood constituents. So for instance also creatinine. At this point there was a discussion of were there creatinine in human blood at all or did the kidney synthesize this? You could see it was also in the muscles, but it was hard to measure in the blood. So a lot of this is at the forefront also of measuring and being precise in measurements. And while doing this work, Reybert invented a precision technique for titration, which is called the Reybert burette. And it was sold throughout the world in the 20s and 30s. And it actually did a lot of funding the research at Corst Laboratory. So that's also a part of this story.
Speaker 2: So Tobias, maybe we're at a good point just to make sure we've covered everything in this story. So what have we not addressed that you think is important for our audience to know?
Speaker 1: Well, I think it's important to realize then that what Rebert has now done is that he has provided a method and an approach to measure the glomerular filtration rate in a reliable manner and has developed the techniques you could say so that he can, so that those measurements can be made both. in experimental settings, but also in the clinic. So it now can become a useful measure. And then it is now up to, you could say, the renal environment, the kidney environment, to make use of this and to accept the idea that such large amounts are in fact filtered and that filtration is, you could say, a major component in at least starting the pre-urine. The concept of secretion remains controversial. for the next 10 years. And to what extent does it happen? I did not actually believe in it happening. And I think this is, in my opinion, one of the places where comparative physiology played a fundamental role because there was the identification through American researchers of fish that lack a glomerulus in the kidney, meaning that the fluid that they excrete in the urine must have arisen by secretion. So it's a way of demonstrating that secretion is at least in these animals, the mechanism or the Ave. you could say, for creating the urine. So I think over the next 10, 15 years after a bad publication, it becomes solidified that all of the three processes that we now teach in our first kidney lecture in universities, namely filtration, decrease and reabsorption, that they all contribute. And going back to the choice of animals, I do think it is interesting that there implicitly was the assumption that what you find in a fish, what you find in a frog, what you find in a human, they are the same processes. And we have to remember that at this time, the evolution by natural selection proposed by Darwin, it was not universally accepted at this time. So there was no a priori reason that we had to be all that similar. except that you could say that it's basic physics. I think it's difficult to think of other processes, but the idea is that we can translate what we find in one organism to another organism. And that then solidifies before the war.
Speaker 2: Right. So before we go to the war, Henrik Dimke, I just want to give you an opportunity to add to Tobias's comments.
Speaker 3: No, but I think one interesting portion also after this publication in 1926 is that After that, he actually starts working with patients that have nephritis or impaired kidney function, you can say. And with Kai Halton, who's another Danish doctor and researcher, he actually publishes a few papers in 1928 and 31 where they look at healthy individuals and they say that overall it seems that these healthy individuals seem to have a filtration rate above the 100 milliliters per minute. But they find that many of these patients that have the renal disease, they seem to have a substantially reduced filtration rate. And they also say that this reduction actually seems to occur before they can see changes in blood urea. So I think they're already, probably without knowing, but they're already actually pushing the field quite substantially towards what we are now seeing, what has been seen in patients and how good the And laminar filtration is as a marker of kidney function in general.
Speaker 2: And Henrik, just the article, your editorial ends with what happens to Reinborg during the World War II. Why was he imprisoned?
Speaker 4: He took part in resistance work from about 1943, mainly gathering information and sending these informations around in Copenhagen. There was a big network of resistance people at the university and Reiber was a very central person in that. In early forty-five, that's like 3 months or four months before the liberation and the end of the war. This group gets caught And they all end up at the top of the Gestapo headquarters as a human shield in order to, say, avoid British bombers attacking the Gestapo headquarters. And so they said that they are, some of them are tortured and they are interrogated very hard physically for a month or so. And then the British attack in early March and people Some of them survive and get out, and Reber flees to Sweden together with a couple of other guys. So it's a very dramatic history, and Reber's back was actually one of the physical signs that showed what went on in Gestapo, and there was a physical torture of Danish prisoners in Denmark. Reber himself thought that he only survived this heart interrogation because of his knowledge of shock phenomena. He was at the very limit during that month or so that he spent in prison. And of course, with that sort of history, you would get a lot of, you would be a very influential guy after the Second World War. instantly got a place to speak from and tried to raise the things that he wanted to. So for instance, he worked hard for young scholars and young scientists in Denmark to create funding opportunities and scholarships and research grants from the government. That's what he used his influence to gain. So Tobias, you had mentioned earlier about how important.
Speaker 2: Denmark is to physiology, to renal physiology. I'm just wondering if you can help us take this moment and just apply it as to how it's affected sort of history and how you think of the specialty in your country.
Speaker 1: I think what Reiber ended up doing as a very loud and clear voice for science in Denmark was that he was Unlike most scientists, he was good at talking to politicians and became a politician himself, you could say. So he was able to advocate the value of education, the value of securing, as he like said before, the education of young scientists and the promotion of science towards younger scientists. in a very effective manner. And he set up the whole concept of us having a research council. Obviously, research councils were also created in many other countries, including the United States, after the Second World War. But Rai Baer was very instrumental in doing so in Denmark. So I think he had a strong voice in terms of advocating science in general, both to the public, but in particular to the politicians, where it translates into a real effect. And as a physiologist, of course, he was a good, you could say, role model for physiology as a field and as a chair of the Karzberg Foundation, which at the time was the biggest private foundation in Denmark. Now there are other foundations, but it has historically been the strongest foundation in Denmark. So by chairing that, he was also immensely powerful because it's a small group of five people who decided who they would award that support for. So I don't think it's difficult to imagine that for physiology, he's been a very good person to have sitting there at that table. So I think he's part of our great history of physiology that is obviously built, I think in particular on I would call, but certainly continued by Heiber.
Speaker 2: So Henrik Dimke, I'm going to give you the last word. If we can take something away from today's conversation and your editorial and just your interest in this story, what's your summary? What's the key thing for us all to remember?
Speaker 3: How I interpret this is that Reba really, he set out to understand something and he ended up really changing the field to a certain way. At least he partook in that process. And I think that is immensely important that you have the ability to go after something like that and then stay with it, be able to stay with it, and then in the end transform it into what he did. I think that story also really deserves to be known. That's why we took the opportunity to celebrate this continuum in form of a editorial and also, of course, very happy to participate in this podcast.
Speaker 2: Great. Well, thank you very much. I really appreciate your all taking the time and I really enjoyed the conversation and the editorial was great. So thank you. Thank you for listening to this podcast by the American Society of Nephrology. I'm Tad Ibrahim, Chief Executive Officer and Executive Vice President of ASN. This podcast should not be used in any medical emergency or for the diagnosis or treatment of any medical condition. If you have any questions about any medical condition or before taking any drug, changing your diet, or commencing or discontinuing any course of treatment, please consult your doctor or another qualified healthcare professional. Views expressed on this podcast are those of the speakers and not necessarily those of the American Society of Nephrology. This podcast should not be used in any medical emergency or for the diagnosis or treatment of any medical condition. If you have any questions about any medical condition or before taking any drug, changing your diet, or commencing or discontinuing any course of treatment, please consult your doctor or another qualified healthcare professional.
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Episode URL: https://www.asn-online.org/media/podcast.aspx?ID=672