APRIL 26, 2002

JD:  I’m John Dirks and I’m here for the International Society of Nephrology and it’s Video Legacy series. Today we have an opportunity to talk to Barry Brenner here at the Brigham & Women’s Hospital Harvard Medical School in Boston and we’re going to discuss what has happened since the International Society or ISN was founded in 1960.  We will talk about the evolution of contributions and advances in basic understanding of renal disease, clinical aspects of renal disease, how they all came together and touch on some of the global issues that are current now in the year 2002. So Barry, it’s great to be with you and maybe you want to make a comment and introduce yourself.

BB: It is a great honor for me to be included in this Legacy Series, and I especially appreciate the chance to have this chat with you John. We’ve been friends for more than 40 years and in fact, we first met, I remember it quite vividly at the NIH, where you were finishing your fellowship in the Kidney and Electrolyte Metabolism Lab led by Bob Berliner and I was just coming for an interview to see if they would take me for that laboratory. You finished up and I came in a year or so later and we’ve both been blessed by the benefit we’ve enjoyed over the years from our training there, a very special time in renal science and medicine. In some ways it was at the launch of scientific nephrology.

JD: Well, I would agree with that and I remember that occasion well when you came and this was the start of a tremendous, impressive career that you’ve had. It’s interesting Barry to reflect as you just did on the issues that were at hand, as I recall some of the basic measurements that proved the counter-current system for concentration and dilution of urine had been established. Another series of compositional measurements had been made regarding sodium, potassium, other ions along the nephron, but at that time began the whole story of volume regulation and micropuncture was in fact the technology of the day. I wonder if you want to start off by how you got involved in that?

BB: In the 1960’s when we both were receiving our training, the scientific basis of nephrology was really governed by the work that had been done over the prior 50 years, mostly with clearance techniques…

JD: Right.

BB: Given limitations in technology, the kidney had been approached as a black box. We knew what went in, we knew what came out and we inferred a good deal about mechanism. The interest in trying to get down to the nephron unit actually began in the 1920’s with A.N. Richards and his colleagues in micropuncture studies recognizing, as Richards did, that if you want to access single nephron units you had to work with microtechniques and he developed the techniques including micropipettes that could be inserted into tiny renal tubules and that required micromanipulation devices in order to transfer coarse human movements into very fine microscopic movements, but he worked with amphibians.

JD: Right.

BB: And we gained important insights from his early studies, but the approach was so technical and was discontinuous in its development that for about 25 or 30 years the technique laid fallow. It was picked up again to answer specifically the question about urine concentration and dilution, through the work of Dr. Carl Gottschalk…

JD: In the 50’s.

BB: His enormous contribution was in sampling from the rat kidney some accessible loops of Henle and finding in the ascending limb of Henle that the fluid was less concentrated than plasma.

JD: Right.

BB: So the dilution step carried out by the active transport of sodium as we know it now by the ascending limb, served to dilute the urine and that laid the basis for rigorous confirmation of the Wirz, Hargitay, and Kuhn hypothesis about how the counter current system could lead to progressive dilution or concentration of the urine.

JD: Its fair to say that the evidence that they gathered has stood the test of time.

BB: I think it was decisive and also showed the power of using these microtechniques to address questions that could only be answered in the level of single renal tubules. Giebisch adopted the technique soon after Gottschalk and began to ask questions more related to ion movements along the nephron as a function of distance from the glomerulus and his beautiful and painstaking studies are as valid today as when they were published in the 1960's and these are now classics. And any student of nephrology coming into the field must, of course be, gain access to those wonderful, classical papers and become familiar with them.

JD: And Gerhard Giebisch continued to illuminate these studies…

BB: To this day.

JD: Yes. Let's move into the time when you and I were at NIH and the questions asked then. There was a great expansion of micropuncture, there were new techniques that came on board and we now went into the issues of volume regulation and the issues of control. We had sort of taken a jump forward in terms of the kinds of questions that one could ask. I wonder if you might dwell on that for a minute?

BB: I think when these techniques were going from the whole kidney to single nephrons in vivo, when these techniques became part of the routine of some of the laboratories around the world, in Berliner’s laboratory at Bethesda, in the Seldin/Rector laboratory in Dallas, in the Ullrich’s laboratory in Germany…

JD: Yes.

BB: To name just a few.

JD: Yes.

BB: People sort of gravitated to a piece of the large question of what the kidney does. So in Dallas there was a great interest in how the kidney regulates acid base balance.

JD: Exactly.

BB: And in Ullrich’s laboratory how the kidney modifies the blood composition of glucose and amino acids, and often organic solutes. And in the laboratory we came from, in Bethesda, the interest was in extracellular volume regulation. Not exclusively, but to a large extent. And you know a major role of the kidney in health and in disease is in fact setting, not only the composition of the extracellular fluid, but also the volume. We see breakdown of that delicate regulatory mechanism with acquired renal disease where you either retain too much sodium and water and develop edema or you loose too much salt and water because of failure of transport mechanisms along the nephron and thereby imperil the stability of the circulation. So how did the questions get addressed using volume as a theme?  Exaggerated shifts of volume were induced experimentally. We gave litres of saline to a dog in an hour…

JD: Leading to massive diuresis…

BB: Or we induced hemorrhage or diuretic-induced volume contraction and it served to unbalance the system deliberately and we then saw what mechanisms were brought into play. And then what did it take to fix…the alterations. And, your studies which really brought not only clarity to the subject of volume regulation with regard to role of the proximal tubule, but in some ways it shocked the spectators because everybody thought that the volume would be regulated only in the most distal portions of the nephron where the fine tuning would be occurring and you showed major influences on volume regulation by proximal tubule adjustments.

JD: Yes I remember those moments well when people like de Wardener, Lou Welt, Ivor Mills came to NIH and were very excited and surprised as you said. But it’s not to say that later on everybody wasn’t right in many ways. But then the debate started as to whether these changes with large increments in volume or decrements in volume were mediated hormonally and that set up a whole interesting time determining whether it was mediated by physical factors and you were very involved with that…

BB: Yes I was…

JD: When you went to San Fransico.

BB: Well even before, it had been the case that in addition to regulation of extracellular volume through changes in glomerular filtration rate and through influences of aldosterone on the kidney, which served to regulate sodium reabsorption, was there yet another factor or set of factors that could regulate volume? ie: could there be a hormone manufactured in one part of the body that reaches the kidney, the hormone being turned on or turned off by changes in extracellular volume status? This thought of a third regulatory pathway was in fact dubbed the third factor…

JD: Right.

BB: And we now know that there are regulatory hormones for volume. Some of them are made in the heart, ie:  atrial natriuretic peptides. Some are made in the brain, brain natriuretic peptide. But brain natriuretic peptides are also made in the heart.  These are pluripotential peptides, if you will, coming from many different sites that regulate volume by regulating sodium and water transport in the kidney.

JD: Exactly.

BB: And in fact some proponents said yes and some who couldn’t reproduce the experiments said no and in fact both were right and both were wrong as is usually the case when very good groups differ and fight about it they’re usually both right and somewhere it takes time for the groups to come together. This took longer than we had as during our Fellowship years, but it took place over our entire careers.

JD: Over our careers…maybe just to finish that thread a bit because you and I recall the excitement and the disappointment respectively as people sought for this third factor, imagining something rather different then eventually was proved. Just to finish the thread in terms of the hormonal control. You mentioned atrial natriuretic factor in the heart and the brain. Is that the story now in 2002?

BB:  I think the natriuretic peptide regulation of extracellular volume is unequivocally demonstrated, but that doesn’t mean there aren’t going to be other candidate regulators as well. To some extent prostanoids influence salt transport in the nephron and play some regulatory role. Vasopressin plays some role and of course aldosterone is a key player. I would certainly not want to conclude in the year 2002 that we know all there is to know about volume regulation including hormonal controls. I’m sort of reminded of the Solvay Congress in 1898

JD: Right.

BB: In Belgium where the nine physicists who attended that Congress, being a closed club of invitees, one after another said basically, "Gentlemen, everything that needs to be known in physics is known" and that was seven years before Einstein published the Special Theory of Relativity which completely overturned all that was known.

JD: Well I agree.  We recently heard the opposite in an address of a genome scientist who said, "We only know 1% of what we are going to find out in the succeeding years." So that deals in terms of extracellular fluid regulation with some of the currents that happened in hormonal control. We had a very big set of studies that you’re intimately involved with and others dealing with the so-called pertitubular, the physical factors. I wonder if you might trace that a bit?

BB: That was basically the thrust of the research I did during my Fellowship and then in the first few years in my own laboratory in San Francisco in the late 60’s and early 70’s. I was very interested in the role of the properties of the blood as the blood flowed through the glomerulus because the glomerulus is really a separation filter. So the substances that are filtered are small molecular weight, crystalloids and water. What’s left behind in the blood flowing through the glomerulus are the larger proteins in the plasma and also the formed elements, the red cells, the white cells, the platelets. I don’t think everyone appreciates how much of a step up in concentration occurs to those substances that don’t get filtered. For example, if the hematocrit going into the glomerulus is 45 volumes %, roughly the normal human value, the hematocrit coming out of the glomerulus is 65 volumes %.

BB:  One could calculate from filtration fraction what that the post-glomerular hematocrit was, but I felt compelled in those early days to actually measure the hematocrit in post-glomerular blood vessels and showed that it was equal to what we had calculated. The protein concentration going into the glomerulus, total protein concentration, 6 or 7 g/dl. Coming out, 9 or 10 g/dl. Well the stepup in protein concentration leads to an even more exaggerated step up in the colloid osmotic pressure because there is a nonlinear relationship between concentration and the colloid osmotic pressure. This creates, as a result of glomerular filtration a concentrated post-glomerular environment as a consequence of that filtration where you now have unbalanced the Starling forces enormously in favor of returning the fluid back into the vessel because of the pull of the osmotic forces, these oncotic forces. Having thought about that a bit, I didn’t see that we had clear understanding of the contribution of these stalling forces downstream to the glomerulus. And so we, Julie Troy and I and my fellows in those days, carried out experiments where we could show direct correlations between the height of the peritubular capillary oncotic pressure and the rate of net fluid absorption, across the proximal tubule. And in circumstances where that step up is even more exaggerated than normal, as in heart failure where the filtration fraction goes up, the exaggerated retention of salt and water, that’s characteristic of the failed heart, is also driven. So the correlations worked beautifully and gave us enormous confidence in our ability not only to define these Starling forces, but to show how they regulated net fluid absorption.

JD: Barry, those were very impressive experiments and I wonder if you, looking at it today, here in April 2002, how do you sort of summarize the role of these peritubular factors via the proximal tubule reabsorption? It’s a remarkable system actually.

BB:  I see the proximal tubule as an epithelial cylinder with luminal content to be processed by absorption and secretion. For the pathway for absorption I still think the model put together by Bossert and Diamond still holds.  This standing gradient for driving fluid absorption across the epithelial cylinder, but the fluid has to go from an interstitial compartment on the other side of the proximal tubule into the local circulation.

JD: Yes.

BB: So that’s where the Starling forces act across the peritubule capillaries. To govern the net uptake of fluid or the rejection of that uptake and therefore more back leak of filtrate returning to the tubule lumen, in a sense diminishing net fluid reabsorption. So it’s a regulatory pathway that helps in concert with the active transport across the epithelium to control volume balance. That is where we were when it was discovered in Europe that there were rats that had glomeruli on the surface.

JD: That opens a whole new chapter in terms of glomerular function.

BB: Because until that chance finding in 1970 the only accessible glomeruli to the renal physiologist were in the plate-like kidney of the amphibian, which is why Richards did micropuncture in frogs. But if you are interested in mammalian fluid regulation, how do you gain access to the glomeruli? In mammals, the glomeruli are usually buried within the substance of the kidney and remote from the surface, which is where the micropuncturist gains access to the kidney. When I was on a visit to Germany one of the active laboratories there, one of the members of that laboratory, happened to mention to me in an offhanded way that they had discovered some rats that had AV malformations on the kidney surface.

JD: Were they called, AV malformations?

BB: So I said I’d be very grateful if would send me…

JD: Yah.

BB: A few rats from this colony that had these AV malformations, because I immediately thought that these cherry red spots were glomeruli. I didn’t quite say exactly what I had in mind when I asked for these rats

JD: Yes.

BB: And I remember vividly…they were generously supplied, they were put on a Lufthansa flight from Germany to San Francisco. I went to the San Francisco Airport to the cargo facility for Lufthansa to claim these rats. The bill of lading said there were a dozen rats in the cage and I counted eleven. I chose never to fly Lufthansa after that for fear of some rat being on that plane eating through the cables. In any event those rats confirmed my suspicion and one of the things I did first with Julie Troy, my associate of many years, was to take a kidney out of one of them and make histologic sections to show histologically that some glomeruli were at the surface, in fact the capullaries of those glomeruli were separated from the micropuncturist by the renal capsule, which is a single cell layer, which we usually strip off. So these glomeruli were right on the surface and within reach of micropipettes.

JD: Now Barry, that was a very special moment and a very exciting one. I remember reading all the papers and you were alone in studying the mammalian glomerulus and you worked out and codified all fundamentals of glomerular filtration. And we’re going to come back to the clinical side later, but I would take the view that this was a very important forerunner of important clinical applications later on, but lets return to the physiology.

BB: Well the physiology is only made possible by the technology. So why did I want those rats with accessible glomeruli? It turns out that to study the peritubular capillaries and the appropriate Starling force measurements, we needed to measure the hydraulic pressures in the capillaries and the oncotic pressures based on the protein concentrations. And we had been developing techniques to do just that. We had now an online system for the real-time measurement of pressures and capillaries using a servo-null device, which enabled us to trace in a single capillary the 300 beats per minute, that is a typical heart rate of a rat under anesthesia, and with a signature for the peak to trough in the pressure wave that was as accurate in fidelity as if you had the catheter in the heart. In fact I used to joke to my fellows that if rats had aortic stenosis we could diagnose it at the capillary level. That’s how faithful was the trace. Well we had those techniques. And when the AV malformations on the surface on the kidney became known to us, we could do something about it because not only were these accessible, but we had the tools. And you’re right, for a honeymoon period of about two years we were alone. That meant we had the monopoly on these techniques and the animals. We gave the name of the rat a new name, it was a Wistar rat and we named it for the city in which the discovery of the surface glomeruli was made. We called it Munich-Wistar rats. I did that because at the time hemoglobins were being named for the cities in which the hemoglobin abnormalities that were found in those days, commonly now, were named. So I thought this was a nice way to honor the people who really discovered this and should get the credit for it, people in Klaus Thurau’s laboratory.

JD: Now it might be good just to summarize some of the key observations, because we’re going to get back later to the hyperfiltration story, the glomerular hypertension story.

BB: When we put the first pipet into a glomerulus (and Julie Troy has the trace and we have it framed and mounted), the pressure was low. The textbooks built on no direct measurements at the time said that the glomerular pressure in an animal with a systolic blood pressure of 120 mm of Hg would be 90 mm of Hg. We measured 45. So I said with our first measurements we must have miscalibrated so lets go back and recalibrate…the calibration was correct and it was 45. And in the next glomerulus it was 45. And in the next animal the glomerular pressure was 40-50. About 15 mm of Hg above the inlet oncotic pressure of the blood so the excess of hydraulic over oncotic pressure accounts for the net fluid shift from capillary lumen to the Bowmen’s space. And actually that pressure gradient dissipates along the glomerulus as the oncotic pressure of the blood rises. It actually rises to a value that nullifies the hydraulic force and we then used an old phrase that appeared in the writings of Homer Smith where he posited the possibility that along the glomerulus you might dissipate the net driving pressure and create a situation of filtration pressure equilibrium.

JD: Right…not a foresight by…

BB: And then we had measurements and measurements, but we needed help with the modeling, the mathematics of nonlinear equations to describe the rates of change of oncotic pressure and hydraulic pressure as a result of the fluid shift along the glomerular capillary and I was led to contact a chemical engineer. I was at the University of California in San Francisco and I was put on to a very good chemical engineer, young person, same age as I was at the time, who had this mathematical skill and the computer capabilities to do the modeling. His name is Channing Robertson, he is now a very highly regarded professor of chemical engineering, and he immediately saw the excitement in what we could do with the measurements and assigned a graduate student named William Deen, Bill Deen, known now in nephrology generally for his enormous contributions to mathematical approaches to describing physical phenomenon in the kidney. And his PhD was the glomerulus and his work over the years in physiology has focused on the glomerulus. So we had this enormous, exciting environment.

JD: Barry, you’ve always had the gift of finding people who would advance the measurements you were making at a time, Channing Robertson and Bill Deen are good examples and you had others maybe later and then you have Julie Troy who to this day has been with you for this whole period of time.

BB: Yes. Julie was there when you were at NIH.

JD: Yes

BB: She was there when I got to NIH. I spent three years there and she was my associate there. And when I decided to move out to San Francisco she was at the time thinking of also relocating. She had been in the Bethesda area for seven or eight years and wanted to see what the rest of the world was about and so I was fortunate that she agreed to come with me and I would say our sailing has been fantastic. I would also say that without her I would never have left the shore. She was absolutely crucial to our process.

JD: So there’s a common saying that discovery really depends not only on ideas, but technology that matches it at the time and I think the same thing is true for matching with talented colleagues at the same time. This whole understanding of glomerular function I think was really a monumental series of experiments, but it has now gone on to lead to disease models in which this was very importantly gone into, which has had I would say global ramifications. You may want to insert some other part of the pathway, but this takes us into Boston perhaps, and perhaps you’d want to…

BB: Well, when we were still in San Francisco as I said we had this territory almost exclusively to ourselves for a couple of years and then others came in. Notably Roland Blantz.

JD: Yes.

BB: And then several other groups and there was enough work for all of us. I was first interested in characterizing the glomerular wall. What was its’ conduction to water? What was its’ pressure gradients? How did those change with changes in blood pressure where we deliberately modified the animal’s blood pressure with vasoconstrictors, vasodilators, and looked at single glomerulus auto-regulation? So we did the hard work. We got the story worked out. It was early in the series of studies we did where we asked the question, and its based on the fact that, purely on the fact, that before I did this renal physiology training I was an internist in training clinical medicine. And I saw the opportunity because of my clinical background to do studies that could come from the bedside, questions from the bedside, brought to the bench. One of the questions we asked for the glomerulus was, what happens when you take a kidney out? Everyone knows that the other kidney grows and the function of the other kidney expands. We see it in normal, healthy kidney donors. Take out a kidney and a month later the remaining kidney has grown by 40-50% and its glomerular filtration rate has risen by 40 or 50%. Well what is that adaptation all about? In asking that simple question we found that the adaptation was mostly an increase in glomerular blood flow to the single kidney and a rise in pressure. Now taking out a single kidney in a healthy human being doesn’t cause serious, long-term damage in most donors. I believe, to jump way ahead, that there is some modest price paid even in healthy subjects because over time you see a trend toward higher systemic blood pressures and in many normal donors you begin to see some increase in the amount of protein escaping into the urine. Well, we saw that this compensatory hypertrophy process was accompanied by a modest rise in glomerular blood pressure. 45 in normals went to 50, 52mm of Hg. Didn’t pay much attention to it when we first found it, in fact we wrote a paper talking about the mechanism of compensatory hypertrophy. But then I was, I continued to think about that and that led to the next question, but many years later. What happens if you take out not one kidney, but one kidney and a little bit more of the renal mass?

JD: The remnant kidney.

BB: In other words, what if you used surgical ablation to simulate nephron loss from disease? Then I quote the saying because disease injures all the tissue whereas surgical oblation removes tissue but leaves behind normal tissue. Well in fact it was shown in the 1920’s by Newburg and others that ablation of more than one kidney leads to impressive hypertrophy of the remnant, but over follow-up of weeks the normal kidney tissue that’s left behind undergoes transition to abnormal by a very deliberate, monotonous process of progressive segmental sclerosis leading to global sclerosis in the glomeruli left behind following the surgery. Well isn’t that what we see in our patients in the clinic who have renal disease? They progress. Monotonously the kidney function gets worse and worse, the GFR falls progressively, the scarring gets worse and worse, and the segmental sclerosis evolves to global glomerular sclerosis. That’s when the light went on and with Tom Hostetter, Tim Myer and Sharon Anderson as fellows, names of people who have had very distinguished careers, we all were engaged in something that was phenomenal. A parallelism between what happens following surgical removal of renal tissue and the progressive loss of renal function that we see in our patients with kidney disease as we follow them over time. When we took out more than one kidney, the pressure in the remaining glomerular capillaries didn’t go up by 5 mm of Hg, it went up by 10 or 15 and it raised immediately in our minds the question…Is that increment in glomerular pressure as harmful to the glomerular capillary as a rise in blood pressure is regarded to be harmful to the vessels in the arterials and small arteriols in hypertension generally.

JD: And you also used other models, like diabetes.

BB: That came after this.

JD: Yes.

BB: Here the central question was…is progressive renal disease driven by the adaptation to high pressure? We dubbed that "glomerular hypertension" and we simply said…how can we lower the pressure even though we took out the kidney tissue? And that again harked back 50 years to the studies of Newburg and others who showed that if you took out kidney tissue, but at the time you placed the animal on a low protein diet the expected hypertrophy didn’t occur. So we wondered whether the absence of hypertrophy would also mean the absence of the glomerular hypertension now superimposed? And when we did the low protein feeding following ablation indeed there was no hypertrophy, indeed, there was no high glomerular pressure, and in subsequent follow-up of those animals no progressive deterioration of structural function of the kidney. So it’s not loss of nephrons that leads to end stage renal failure, it’s the adaptation to the loss of nephrons, which we found could at least in part be hemodynamic.

JD: Right. So that was blocking the adaptation and you went into studies that actually were directed at the glomeruli hypertension itself.

BB: When we looked at what it was that was most noxious there were two changes that occurred with renal ablation, the glomerular pressure went up and the glomerular blood flow to the remaining glomeruli increased. It turns out that the blood flow increase is not perceived as harmful, but the pressure is. We could see that by selective manipulation of each of these. The low protein diet worked as a treatment. Hark back to the observations of Addis in the 30’s who was prescribing a low protein diet to his patients at Stanford. In fact I have a letter on my wall here in my office from Linus Pauling telling me that he, when he was a young person, had glomerular nephritis and he was seen…

JD: By Addis.

BB: By Addis who placed him on a low protein diet. And his kidney disease didn’t progress, as you know he lived into his 80’s, won two Nobel prizes so was not encepholopathic by any means…

JD: But just missed the double helix.

BB: Addis was doing this and it worked. The Brigham Hospital where I work, where we’re now sitting, was founded in 1913. The first chief of medicine was Henry Christian who came from Hopkins where his interest was low protein diet for people with advancing kidney disease and together with a younger colleague Dr. White established here at this hospital a clinic for patients with kidney disease where they were fed extremely low protein diets to the point of malnutrition, but it slowed the progression of their kidney disease. And remember there was at the time no artificial life support in the form of dialysis or transplantation, so the dietary approach to kidney disease was in place. We lost sight of that and it came back in the 50’s when these low protein diets were used in patients who now were on maintenance hemodialysis to minimize some of the toxicity of the uremic state. Very unpalatable diet.

JD: The effects of protein restriction were clear…

BB: But I knew it wouldn’t be widely adopted..

JD: No and so move on to therapeutic side.

BB: So if, if the benefit of the low protein diet was to lower the glomerular pressure, can’t we lower the glomerular pressure with a pill? We have blood pressure pills. They lower blood pressure. So we went through a systematic analysis of different classes of anti-hypertensive drugs, but we started with a new class, the ACE inhibitors.

JD: That was the first one…

BB: Why, because I had already shown in my studies with Bryan Myers and others that angiotensin II, the molecule who synthesis is inhibited by ace inhibitors, is a key component of that adaptation in high glomerular pressure. So of the various drugs that were available for lowering blood pressure we immediately inferred that we might get the biggest benefit with the ACE inhibitor as opposed to some other drugs that could lower blood pressure but don’t work in the kidney the same way. And in fact that’s what turned out to be the case and we could be as protective in our rat model of ablation with ACE inhibitors as we were with dietary protein restriction. But now we had a treatment that would not be as difficult to utilize in the clinic as a dietary restriction because you know its hard to get people to give up beef steaks.

JD: So the ACE inhibitors and their successors have been specifically valuable in reducing glomerular hypertension, but you also explored other disease models.

BB: Again you know my clinical interests, my background. What does all this physiology have to do with disease and its minimization and how can you help people? So what’s the most common form of kidney disease today? It’s diabetic kidney disease, an epidemic that we’re faced with. We’ll come back to that I’m sure. What is the nature of the noxious adaptation in diabetes that leads to a progressive glomerular scarring and renal failure? Roberto Zatz from San Paulo, Brazil was instrumental in these studies along with Tom Hostetter. We began in a climate where hyperglycemia, metabolic abnormality per say, was what was thought caused the kidney to scar. So we did a very simple experiment. We induced hyperglycemia in rats by poisoning their islets with streptozotocin. The animals quickly become insulin dependent and then depending on how much insulin you give the animal as replacement therapy you can set the blood sugar at perfectly normal, in other words complete control of the diabetic state, you can set the blood sugar at twice normal or you can give no insulin and blood sugar will be 600 mg/dl. We chose 200-300 because that’s where most diabetic patients operate. We gave some insulin but not enough to normalize the blood sugar. The animals developed glomerular injury. We kept the blood sugar at 300, but we normalized the glomerular blood pressure, which rises with hyperglycemia because of the extracellular volume expansion. So you get capillary hypertension in diabetes. You get it in the kidney, you get it in the eyes, you get it in all the capillaries of the body when there’s hyperglycemia. Capillary pressure elevations we said were damaging. By reducing those capillary pressures back to normal with ACE inhibitors in diabetic animals whose blood sugars still remained at two or three times normal, we saw much less diabetic kidney disease in the rat. So it was not the metabolic abnormality per say, it was the hemodynamic response to the metabolic abnormality. And that was kind of a revolution in diabetes research.

JD: Indeed it was and isn’t it fair to say that in a general diabetic population 30-40% will get diabetic nephropathy some 5-30 years later. So this had very far-reaching implications clinically. Now we’ve come from very basic measurements starting off with the glomerulus and peritubular absorption factors early on and we’re now down to a pathophysiological observation that has major clinical implications. Now what about studies in the clinical setting?

BB: We said, stop thinking about glucose control as a solitary agenda in management of diabetics and address the blood pressure problem. Now it turns out that in any diabetic, type I or type II with kidney disease, hypertension is the rule. Upwards of 90% of patients with some kidney disease in diabetes will be hypertensive. In the 70’s and 80’s if you looked at the level of blood pressure control it was rather poor, 160/90 on treatment. Now we believe from very good studies that the target blood pressure must be 120/70. 160/90 is severe hypertension for a diabetic.

JD: A new yardstick has been established.

BB: Now I frankly stayed away from the first clinical studies for the reason that I has so much invested in the hypothesis that glomerular pressure was the root cause of diabetic nephropathy and not glucose per say that I thought I would serve my cause best by not being a player in the first clinical studies. The collaborative group led by Ed Lewis undertook a study in 409 Type 1 diabetics beginning in about 1988. That’s about four years after we published our studies in rats. And they randomized his 409 patients into two arms, one group given conventional anti-hypertensive control in addition to insulin and the other standard therapies, the other group given the same standard anti-hypertensive drugs plus the ACE inhibitor Captopril. So the active treatment arm was standard care including standard anti-hypertensives, that meant alpha blockers, beta blockers and diuretics at the time plus ACE inhibitor and the placebo group got alpha blockers, beta blockers, diuretics, but no ACE inhibitor. Studies went on for about four years at the end of which the end points of doubling of serum creatinine as a measure of progression or reaching the need for dialysis was significantly fewer in those given the Captopril than in those given the placebo. Highly significant difference, rapid FDA approval for Captopril as the first line therapy in patients with Type 1 diabetes. Certainly proof of principal. And I have also hanging in my office the New York Times article celebrating that study. It was published in the New England Journal and the newspaper also interviewed me because she was told by various of the people she interviewed that she should go back and talk to the guy who’s laboratory did the experiment in rats to get the thing started. And we were honored.

JD: Well that was a bell weather moment and just trace from that conclusive trial in type I diabetics how this has advanced more broadly and perhaps if you were to take a clinic like yours here at the Brigham, how does this influence practice…

BB: I think it is a very wonderful, personal gratification that virtually everywhere in the world where modern nephrology is practiced, patients with kidney disease, diabetic or non-diabetic, are receiving ACE inhibitor therapy as part of their management for slowing the progression of their disease. That doesn’t mean that we’ve got the magic bullet. That doesn’t mean if your exposed to an ACE inhibitor and you have kidney disease your going to be spared eventual development of end-stage renal failure or the need for dialysis. We still don’t know what the optimal dose of these drugs should be. We don’t yet know for all of the kidney diseases, what the optimal targets of blood pressure control should be. I am sad to say that in many places a physician thinks he or she is doing his job or her job, simply by writing a prescription.

JD: For ACE inhibitor.

BB: Yes, without setting targets for what the drug should do to systemic blood pressure and to the other very, very predictive measure of risk for renal injury, namely proteinuria. We now believe from more recent studies that have been done that the lower the blood pressure and the lower the proteinuria the more favorable the outlook for renal survival. But many patients are receiving such low doses of ACE inhibitors that their blood pressure is not at goal and their proteinuria is still well above the thresholds we think should be achieved. That’s less than 0.5 gram per day.

JD: But there are many gratifying studies. I saw one recently by Wendy Hoy from an island in the South Pacific where there was really quite amazing decrease in the death rate and the incidence of diabetic nephropathy. These were Type 2. So that story has also grown enormously hasn’t it?

BB: The FDA approval for Captopril was in Type 1 diabetes, but of course Type 1 is at most five percent of the total diabetic population worldwide. So what about the majority of patients who have Type 2 diabetes? What’s the treatment? There was no clinical study until September of 2001, the September 20th issue of the New England Journal of Medicine, where two trials were reported. One that I was fortunate to oversee called the Renall Trial in which the Angiotensin II receptor antagonist losartan was used in an active treatment arm of 750 patients as compared to a placebo arm, both groups receiving standard anti-hypertensive therapy, one group getting the angiotensin receptor antagonist, one group placebo. In that trial no ACE inhibitor was used. Part of the reason for studying the angiotensin receptor antagonist and not an ACE inhibitor is that over the years since the ACE inhibitors studies were done we’ve seen that angiotensin receptor antagonists have even fewer side effects that ACE inhibitors. Less cough, a serious problem for example among Asian patients where as many as 60% of them have to be withdrawn from ACE inhibitors because of serious cough. The receptor antagonists have a side effect profile which is as benign as any drug every introduced in medicine. No single side effect statistically different from placebo.

JD: So to stay well within drug charts.

BB: Yes, so that’s why we studied it. And the other study that was published in that same New England Journal issue was a study by Lewis and the collaborative group where they used Ibesartan.

JD: Right.

BB: In Type 2 diabetes these receptor antagonists led to fewer events leading to ESRD, fewer events leading to doubling of serum creatinine. Clear evidence of renal protection. So we now have two classes of drugs, ACE inhibitors and receptor antagonists. Not every disease has been studied with each. Few comparisons in the same patient population of one against the other.

JD: You know all this is very timely. You and I also started in the 60’s when dialysis for chronic renal failure was becoming the practice. Initially in the few limited centers, such as this one, and then it has moved on to a huge array of patients that are being treated in the United States, but at great costs. I believe the annual cost in the United States is something like 20 billion dollars right now and rising…

BB: For this year.

JD: And rising. So if you were for the moment to look into the crystal ball, can one actually reduce the number of patients entering dialysis because we both know simultaneously the incidence because of our lifestyle? Incident diabetes, hypertensive diseases continuing to rise so the number of patients requiring dialysis grows. But do you wish to speculate as to how to really take advantage of this new preventive measure which is what physicians should really be concerned about.

BB: When we analyze the results of the Renall Trial in terms of cost savings, we had fewer patients reaching end stage renal failure with the losartan treatment. That translated into a savings over the course of the three years of the study, if we extrapolate to the number of patients in the United States who also have the same degree of renal disease with diabetes as we enrolled, and we know that number. It’s 600,000 Americans who have Type 2 diabetes and renal disease with a serum creatinine at least 1.3ml/dl. So we know the target population. The treatment, if applied to this population for three years, would save more that two billion dollars annually. Now that’s pitching the savings in the most conservative light. Why, because we studied patients who already had advanced renal disease. The glomerular filtration rates were 40ml/min on the average. What if you started this treatment when the filtration rate is 90ml/min? It’s my personal view that the vast majority of those patients will never reach dialysis. Remember Type 2 diabetes is maturity onset so the average of the population is about age 40-50. If you can defer the progression of renal disease to the point where end stage renal failure requires dialysis therapy, if you can defer it from the present 20 years to 40 years, patients will probably die from some other cause before their kidneys die. So you would have postponement of dialysis indefinitely. That’s where the cost savings would be greatest and that’s obviously where the drugs should be used. We shouldn’t wait for patients to reach a serum creatinine of 1.5 mg/dl before we begin to treat them for progression of renal disease. We need early tests and early markers of those who are at risk. We need to know the genes that put patients at risk. We need to know how to stratify for those risks in clinical trials in order to show optimal efficacy.

JD: Now how do we move from these very clear cut observations in the clinical setting for important diseases like diabetes and hypertension to increasing government decision-maker awareness and public policy? Increasing the ability of physicians to be well trained in this area, to take it seriously, perhaps very early in renal disease? And how do we…we always know that tremendous advantage if the people themselves know that this is a big plus. You know, in my own country Canada, I don’t know if such a policy exists right now? Is there one in the United States?

BB: Well, very soon after the publication of these two important studies in the New England Journal in September of 2001, the American Diabetes Association published in it’s journal Diabetes Care in the January 2002 issue, five months later, a new set of guidelines for the management of patients with Type 2 diabetes and kidney disease and said Angiotensin II receptor antagonists should be considered first line therapy. Five months.

JD: That’s very short as these things go.

BB: So there’s where I think the information translates from the clinical trial to the population at risk - through agencies like the American Diabetes Association, the National Kidney Foundation, the American Society of Nephrology. Now for the international scene, we need to know that the national societies around the world are engaged in these kinds of updates, but the International Society of Nephrology must play a leadership role.

JD: I fully agree, now I might mention that last December the ISN executive selected this as a mission, a global mission to take steps to prevent the development of chronic renal disease, which would involve education, further research studies, partnerships and many other approaches to doing this. So this is now a global mission and you and I both know that in North America the incidence of diabetes and its complications is on the rise because of life style. That rise is much sharper in a number of other regions of the world like South Asia for example. So what is your view as what we should do with the global problem? It was pointed out to me recently that by 2020 there will be 300 million cases of Type 2 diabetes equal to the number of cases of malaria. Already the annual death rate from diabetes in the world is about a million, which is also the death rate for malaria, just using that as comparison. So, this is a good time for us to talk about ISN and not only what should be its mission, but its obligation I would say. I wonder if you might want to enlarge a bit on that Barry?

BB: I think it’s very appropriate that ISN take a leadership position in this problem as kidney disease worldwide is a serious and growing problem before us. Diabetes as you point out is in an epidemic stage now and the epidemic is only going to accelerate. If things stay as they are now, one in three diabetics will develop renal failure. The world does not have the resources, either financial or manpower to cope with renal replacement therapy for the many patients who will come to us in need. So slowing the kidney disease, which I like to think of as remission…

JD: Slowing is remission.

BB: And regression of established kidney disease, actually getting better, are two powerful goals in those who already have kidney disease and then there is the enormous challenge of primary prevention as you say and that means in patients who don’t yet have the kidney disease, the diabetic who has yet to develop micro- albuminuria. If we start by asking the question John by saying, "What clinical data do we have?"

JD: O.K. That should be a first step.

BB: Let me tell you that I have reviewed all of the trials that have been reported. With regard to slowing the progression of renal disease, all kinds of renal disease, studies with ACE inhibitors or receptor antagonists, which are the only two renal protection drugs that we have at the moment, seven trials worldwide, less than 8,000 patients enrolled in total in those trials. And in the trials that are currently underway, but not yet reported, eight other trials with less than 8,000 patients in those trials. So the database is trivial for the issue of remission and regression. What about prevention?

JD: One conclusion is that the research must continue.

BB: So we must grow the research.

JD: Yes.

BB: For prevention trials, less than 2,000 patients are enrolled in the few trials that have been reported to date.

JD: How would that compare to heart disease?

BB: I was just going to bring that up. Contrast that with heart disease where we see published trials yearly involving anti-hypertensive drugs, lipid lowering therapies, thrombolytic therapies, to name just a few therapies. Tens of thousands of patients enrolled in each trial each year reported. So for the United States research enterprise, most of the money comes from NIH or pharmaceutical industry. Well, there’s robust support from those two sources for the cardiovascular trials. And I can tell you that the National Heart, Lung and Blood Institute spends over a billion dollars a year in clinical trials. In kidney disease, minuscule support from the government and inadequate support from pharma. So a major place for ISN leadership is in the lobbying effort to those agencies that have the where-with-all to support this kind of research.

JD: Right.

BB: ISN should lobby with ERA and ETA for the European counterparts. Should lobby ASN for North America with the National Kidney Foundation of Singapore for Southeast Asia and for governments there. In other words right now things are fragmented. There is no unified voice arguing for the need for these trials.

JD: So, I hear two observations here, one is that the clinical information, experimental evidence based on trials is still insufficient.

BB: Inadequate.

JD: Inadequate and it has to be undertaken as a global effort. I also hear a change in direction - for ISN to play this facilitating role with various decision-makers in various countries, in research agencies in those countries…

BB: Not by going to them at the exclusion of the National Societies, but with them.

JD: I think it would indeed be the wise way to work.

BB: Let me bring up another concern. For the graduates of the nephrology training programs in the United States today, the attraction is the financial incentive for going into private practice. That practice is heavily dominated by renal replacement therapy, dialysis.

JD: Right.

BB: A graduate of a program such as ours has the option of joining an established private nephrology group with a heavy emphasis on dialysis and will make in the first year of practice more than twice the average salary for an Assistant Professor in our division.

JD: That’s the case in my country too and I think it reflects Europe as well.

BB: So we are in a competition in a sense. We have only so much manpower reaching maturity each year and the siphoning off of the talent into lucrative practice as opposed to dedicated inquiry in the form of clinical trial designs, clinical epidemiology of disease, rational drug designs, bio-statistics. We won’t have the skilled manpower to even do the trials that are needed. So I’m concerned we need more money.

JD: Right.

BB: We need more dedication to performing the many studies that have not yet to be done that must be done, but I’m concerned about who is going to do them.

JD: In many of the developing countries that you and I have visited, this has to be addressed as many qualified physicians are engaged in private practice just to make a living.

BB:  And there is a lot of research involving clinical studies with only 10,15,20 patients in the study.

JD: Yes.

BB: That’s feasible for an investigator without extensive training. You can ask a question and randomize a small group and collect the data, but the result of that trial is not likely to be convincing, certainly not to any regulatory body. Too small, not enough power to really know whether you have benefit or not.  So we need more large multi-center trials like Renall.

JD: Right.

BB:  In Renall we involved 1,513 patients, in 250 centers in 28 countries. Why, because we couldn’t get them all in the United States? Of course we could have gotten them all here. But we wanted broad geographic representation. Is the benefit unique to Caucasians? Is it shared by Asians? Is it shared by Hispanics? Is it shared by African Americans and other black raced people? You wouldn’t know that if you did it all in one place. So you need comrades who know how to do this and where you can get the data. Retrieving the data is difficult. You need to have manpower, skilled manpower at each site.

JD: So you’re advocating that ISN should be involved in its own way to increase manpower, not only in developed countries, but in developing countries. And in our own countries that we are talking about, there should be a greater investment in those, who I’ll say in quotation marks, are in the "prevention area".

BB: We need to have patient populations represented in trials that reflect the global spectrum of disease. For example, I mentioned earlier that ACE inhibitors cause cough…

JD Right.

BB: In 60% of Asians as compared to 10% of Caucasians. Well, in a sense that’s bringing out a susceptibility gene for cough.

JD: Right.

BB: Well what do we know about the susceptibility genes that make patient A have acute post-streptococcal pharyngitis and develop renal damage and patient B have the same pharyngitis and no kidney damage? Vulnerability genes. For a given level of hypertension somebody develops a stroke, an MI or kidney damage, someone else has a longevity of 90 years with the same blood pressure. What’s the susceptibility risk for patient A vs B? We don’t know yet, but we’re coming to know. I’ll tell you how. The basic sciences that went through this trail we talked about earlier today, from clearance to micropuncture, to micoprofussion, to cells and culture, to the genes that code for the transporters, now to the genomics of various functions of the kidney, transport, inflammation, hypertrophy. All of these are genes that regulate these processes. The genomics allows us to begin to know what genes are brought into play with injury. We need to know which genes are common and which are unique to certain groups in terms of response to injury. So the genomics will actually take us back into the clinic because once we know the genes we’ll be able to say these are susceptibility genes, these are not. These susceptibility genes will allow us to create risk stratification. With risk stratification we can then focus the beam in terms of treatment on those who are at greatest risk rather than those who are at least risk.

JD: So one of the important research agendas has to be the identification of susceptible risk groups.

BB: For the common kidney diseases.

JD: O.K. Now you’re using the word common.

BB:  What are the genes that encode for greater risk of diabetic nephropathy? If one out of three diabetics gets renal disease, why doesn’t the other two also develop renal disease?  The same would be true for other diseases.

JD: Where we do have in common with other medical specialties is in the lifestyle area and it’s interesting just the other day I was reading incidence of obesity in Indians is 30% and who would have believed that? And I’m raising also now simultaneously the issue of environmental factors relating to disease origin. You’ve been very interested in issue of low birth weight for example. There are other environmental issues. Do you want to comment on this a bit?

BB: Well again, what are the things in the genome that predispose use to disease expression? What are the things that bombard us from the outside that modify our genes and our susceptibilities? Well it’s remarkable how overlooked a very simple, obvious parameter has been in nephrology. We’re not all the same height, we don’t all wear the same size shoe, but we’re all assumed to have one million nephrons in each kidney.

JD: Right.

BB: In other words it’s never questioned. You go to the bedside of a patient who has kidney disease or hypertension. Is it fair to ask, "Does this patient start life with fewer nephrons than a patient who has no kidney disease and normal blood pressure?"  Wouldn’t it make sense that the fewer nephrons you have, given the surfeit of sodium and water that we all surround ourselves with in addition to the protein and the carbohydrate and everything else you talked about, shouldn’t the person with more nephrons be less at risk than the person with fewer nephrons? Well it turns out that low birth weight is a major predictor of many things, but it also predicts nephron number. Nephrogenisis stops in utero at age 36 weeks in humans so if your ie:  born at 24 weeks because of prematurity you have low birth weight and you will have the number of nephrons appropriate to 24 weeks, but if you live with the help of a neonatal intensive care unit from 24 weeks and you survive as a neonate, you still only have the number of nephrons that goes with a 24 week old.

JD: It didn’t increase in the ICU?

BB: It doesn’t increase in the ICU.

BB: There is another dimension to this, its called low birth weight of normal genstational age. That’s called intrauterine growth retardation. Well with intrauterine growth retardation the babies have fewer nephrons.

JD: So this is again a population at risk.

BB: Now ask the question. The question begs to be asked. Are those born with fewer nephrons the ones who are likely to become the essential hypertensives at age 30, or in response to the acute pharyngitis the ones who get glomerular nephritis? And carry that through all the way down the line. The diabetic who develops nephropathy, lower nephron number at birth versus the one with diabetes who doesn’t get nephropathy, and this is just talking about one parameter, nephron number. What if it’s not nephron number, but some other correlate of nephron number? Or is it another entity entirely that we don’t even know about. It just means that it’s not all genome. It’s genome plus the environment.  Low birth weight is very common in the developing world. It turns out that the risk of developing hypertension with low birth weight is not in the baby born small who stays small through life,

JD: Right.

BB: It’s in the baby who’s born small and then is allowed, for whatever reason, to be overfed and to be now bigger than normal. In a sense you outgrow your intrinsic capacity. There’s a school of thought that says diabetes is in fact caused by that. You outgrow you islet cell capacity.

JD: So in this case as lifestyle and the local economy improves the individual’s lifestyle or income improves…

BB: And they outgrow themselves.

JD: They outgrow themselves. So we have now touched on a number of key questions globally…

BB: Of international, right global, perspectives.

JD: Yes, where ISN should at least be in a facilitating role, right? Now you and I  spent from the mid 80’s to 90’s, nine years on ISN council and then we were asked to take on this new commission for the global advancement of nephrology, or COMGAN as we have given it the acronym, and we started off with educational courses in the developing and emerging world. I remember the great Moscow launch that we had, and it’s fair to say that this has grown now such that last year in about 30-35 sites, 11,000 physicians attended these various courses…

BB: Sponsored by COMGAN.

JD: Yes, its like having a big meeting here in Boston or somewhere, an international meeting, but now spread over the globe as it were in many smaller meetings. So, this played a very key educational role in places where the physicians actually live and practice and do their teaching.  Now you know we’ve become a global organization, we’re known now for this?

BB: You are global. You do have this social conscience which few societies share. Let me ask a question. Is it time for the ISN to abandon the prior 40 year approach to meetings, which duplicate in many ways the program that occurs in many national meetings each year? Could ISN be more effective by dwelling on not the diseases or the issues that are commonplace in the developed world, but rather that affect more the greater fraction of the globe where the economic level of development is much lower?

JD: Well, that’s quite a burning question actually. In many ways as I just mentioned with our many regional and national involvements and partnerships where we’re carrying out the education and bring along the best people. You come on many of these visits and then there are other leading nephrologists who have joined us…

BB: But I think what we do at lots of these meetings is bring to the audience speakers who can talk about the latest nuance of dialysis or the latest in immunosuppression therapy for transplantation, but few of the patients in those countries where we’re holding these meetings can have access to either dialysis or transplantation because the means of support for those high cost replacement therapies is just not there.

JD: Well I think it’s a good point even though I must say I think it’s increasing, that is the availability of renal replacement therapy and this is a burning issue for the future. I heard a figure the other day for one Pacific Island, renal care costs were 25% of the healthcare budget.

BB: Well how long can that continue?

JD: It can’t.

BB: So then we got to get back to the question of prevention.

JD: And we’re putting that on the agenda all the time.

BB: So, whereas the ASN, or the EDTA, ERA may not be focused on prevention, but more on remission, regression strategies, this could be a powerful role for ISN.

BB: And then we need to interest those agencies worldwide that are also engaged in the issues of prevention. ISN’s role may not be in worrying about sewers and running water, although they are very important, or vaccinations, but renal strategies for at-risk populations that will mute if not sever completely the fuse that allows those diseases to run their course and cause kidney failure.

JD: Well, I agree that we should be trying to place prevention discussions, strategic discussions at various meetings and hold special meetings in this regard. Your question about our biannual congress is a more difficult one and it’s up to the current leadership to address that. Some would say maybe we shouldn’t do that because we have a very high impact journal in Kidney International, which has a lot of basic studies. It’s been a very successful journal for over 30 years, and JASN is another excellent journal, but these two sort of are the leadership journals.

BB: But by the same token Kidney International could put out a call saying they are especially interested in papers produced by the international community dealing with prevention. That doesn’t mean a good molecular biology paper has to be rejected, it means that the scope is broadened, but a major commitment is made toward the issue of prevention.

JD: In each issue?

BB: Yes.

JD: Well I think it’s a very salient point. Now the other aspect of the Congresses deserves study. Some would argue that perhaps they shouldn’t be continued. Others would say they need to be reinforced as the global number of physicians in the field is rising and allows you to shape it somewhat differently. Let me ask you another couple of questions on the global side. Dr. Remuzzi has pointed out that there are a lot of diseases, you know they have different names, rare diseases, orphan diseases, neglected diseases that are also involved in causing renal disease. My colleague in Toronto, James Urbinski who is with the Doctors Without Borders, his direction, his focus is on some of the bad parasitic diseases, River Blindness and so on, but as this also effects renal disease and I understand that more recently you’ve taken this up as a point of interest.

BB: I have become an authority on probably the least common form of kidney disease there is in the world.

JD: And what disease is that Barry?

BB: Fabry’s Disease.

JD: Now remind everybody what Fabry’s Disease is because its rare.

BB: Fabry’s Disease is a lipid storage disease that causes lysosomal abnormalities in many cell types. For the kidney, the endothelium, the mesangium, the podocyte in the glomerulus, the distal tubule cell and the peritubular capillary cell are all involved. They’re all adversely affected and over time the hemizygotes, the classic individual affected by this disease, which is caused by an abnormal gene that leads to failure of production of the enzyme alpha-galactosidase A, necessary for the metabolism of these glycolipids. So the metabolism doesn’t occur, the lysosomal compartments are stuffed with the residual products and it causes damage. So these patients typically go to end stage renal failure by age 40 or 50. There are probably 10,000 patients in the world based on gene frequency. Most of the Fabry’s patients who are on dialysis don’t have a diagnosis of Fabry’s because nobody ever measured the enzyme levels and the biopsy is often not done in patients who have chronic, progressive renal disease. It’s assumed to be glomerular nephritis. Well the reason why it’s a subject of interest is it now is the case that the missing enzyme can be made and infused every two weeks and enzyme levels can be brought to near normal and further lipid accumulation ceases. So the cells remain normal because you have enzyme therapy. So we now have the third proven renal protective therapy. We had Captopril, and ACE inhibitors, then we had angiotensin receptor antagonists, and now we have the first recombinant human enzyme replacement therapy with renoprotective properties.

JD: Right.

BB: For as you say these kinds of uncommon diseases.

JD: Let me make a comment on that. It's interesting to me in our COMGAN travels that if you ask local nephrologists, what are the common causes of chronic renal disease? What do your patients in the renal unit, the dialysis unit have? Now granted that in many cases biopsies are not available. Where they have historical records they usually will refer to various forms of glomerular nephitities and of course more recently, diabetes and hypertension. But then you get surprises, for example in a visit to Indonesia about a year ago, the second most commonest cause in major cities was obstructive uropathy. Now we’ve dealt with that in wealthier countries for a long time, but it indicates that there are other causes of chronic renal disease that are preventable. And then there are rarer diseases such as Fabry's. So that’s one issue. Now the other issue is…

BB: Well just let me make a point here that in the developed world, routine physical exam and laboratory testing, as part of normal health maintenance, is the rule.

JD: Right.

BB: So you have a check up, your blood pressure is measured periodically, the urine is examined periodically for an insurance physical or an employment physical.

JD: A lot of signals.

BB: Things get caught before they become seriously abnormal. In the developing world where there is not this routine of monitoring and examination, patients often present with end stage renal failure. No prior detection was in place and only after the patient experiences devastating loss of kidney function and the side effects, weakness, anemia, bone disease, and on and on and on, do they come to medical attention.

JD: So what is needed?

BB: Screening.

JD: Screening, but also that the developed countries must play a larger role in improving the health services in general in developing counties. Even Jeffrey Sachs recently talked about disease zones. It wasn’t actually the geographic boundaries that were important as much as the disease zones. The second spinoff from your example of Fabry’s that I want to touch on is cost of drugs. We’ve all learned about the issue of HIV and in Africa and there has been some gains on this. But lets take the issue for now in our case of ACE inhibitors and ARB’s in early diabetes. And, lets say we were going to try to implement this in a less well off African or Asian or Latin American country. How can we do this?

BB: I think we take the model that already exists in which big pharma contributes at trivial costs their powerful drugs. For example the treatment of River Blindness…

JD: Right.

BB: Is by donated drug. No return on investment in the country to which the contribution is made. Lets recognize that many ACE inhibitors are now off patent.

JD: Right.

BB: Captopril is pennies a day. The difference between pennies a day and no pennies a day in reimbursement to the company is not going to make or break the company. Get the Captopril where it’s needed and where it isn’t now, because there’s nothing there. What about patients who need artificial life support with dialysis?

JD: Right.

BB: In some parts of the world the government pays for it as in the United States, Canada, Western Europe. In some parts of the world the patient pays what he or she can pay and often it’s sufficient for the physician to enroll the patient in the chronic program. But in the vast majority of the globe, the patient doesn’t have the money, the government can’t do it, and so end stage renal disease equals death…

JD: Yes.

BB: Equals death from uremia. What about donations from those companies that make the plastic tubes and the cartridges, the dialysis membranes?

JD: It’s the consumables as you just figured, which are very critical. Often you get the machines, but not the consumables.

BB: And where can industry help in this hospital and in the hospital you’re associated with? Every few years we completely turn over our dialysis equipment and replace with the newest, but there’s nothing wrong with what we put down in the basement. But we don’t have the money to ship this now redundant equipment to a place in need that has nothing.

JD: You know, I think…we’ve just had one of our first examples of such a donation to Cuba where they have trained staff in their country to utilize this, but there are other places where in fact this capacity needs to be built up.

BB: What if we at ISN were able to say, in a concerted way, along with the ASN and NKF in the United States and Canada, to those manufacturers of dialysis equipment:  when you sell to hospitals the condition for that sale is that you reclaim that same instrument when it is replaced by your company with a new product, you reclaim that instrument and ship it to a facility that we designate? Make it part of the deal.

JD: What I’m hearing here is a challenge to ISN again in the advocacy role.

BB: Far be it from me to challenge anyone.

JD: No, but its, this…

BB: Raises a question.

JD: Price of drugs, pharmaceuticals, the availability of high tech equipment, because I think you and I share the view, which hasn’t always been the view of all the world health agencies, that it’s very important to strengthen the technical and intellectual base in the developing countries so their trained people stay home and don’t migrate to our own countries because we have a vigorous appetite for talented people from all over.

BB: Certainly the ISN’s fellowship program requires that you eventually return to your home country.

JD: And over 80% have and I think that’s very important. Barry, I want to come back to our COMGAN activities. You’ve spent a career in basic and clinical science. Some might not have thought that you would have got fulfillment in going to various places in Asia, Africa, and Latin America, but you did. Maybe you can describe in a nutshell why this became very important to you.

BB: It’s actually more than I can put into a nutshell. It’s a very extraordinary opportunity. For somebody who’s had some success going now to a place where your name is recognized because of the work you’ve done, but where people wouldn’t have thought they’d have a chance to spend time with you or in a small group to ask questions about how you began, how you think, how you reason, what you consider to be the pressing questions in the field, where you think the field is going. And I have found enormous gratification from this kind of interaction. Moreover, I have met so many brilliant young people a few of whom it was possible to help come to either our laboratory or to another laboratory where I could help be a broker in that transaction, to get that person into a training program. And I’m talking about people who when they did their own letter writing to try to qualify for programs, failed to meet success.

JD: Right.

BB: You go and you see people, you meet people, and you recognize their sheer brilliance. What’s missing from their ability to play the Beethoven violin concerto is that nobody put the violin in their hands in the first place. That’s what’s missing. It’s not the ability to then take the instrument to its fullest and I’ve had so many very outstanding people come through our lab on the basis of this kind of interaction. That shouldn’t by itself be the reason one goes. I’m not going as a headhunter to find people to come and bring back. It’s that it’s part of the upwelling of excitement and enthusiasm on the part of the audience and on my part when I take these kinds of trips.

JD: You know, it’s great to hear, you always stress from when you and I started this that we should go there even be proactive saying we’d like to come and visit Moscow, or South Africa, or Ghana, or wherever it was rather than saying I’ll see you at the San Francisco meeting and we could meet and talk about this, but it was to go there and to participate with them and see how they worked. I think that was a very important strategy and it served us very well.

BB: And as you say nothing can substitute for that. If you made a videotape of your lecture and sent it,

JD: Yes.

BB: It would count for almost nothing compared to what you get when you go.

JD: There has to be a person there.

BB: You have to be on the scene. It’s a lot of work. You’ve done it far more now than I have. You’ve continued this active travel schedule to probably 30 different countries a year. Extraordinary and there’s no organization, no international medical organization with a framework such as COMGAN’s. Nothing as mature, nothing as penetrating, nothing as successful. To your credit.

JD: Well and to yours too.

BB: And it’s to the credit of ISN that they see the merit in this, the wisdom. In fact, much of ISN’s agenda is now COMGAN associated, COMGAN oriented, COMGAN's commitment in terms of resources.

JD: I think it was the right thing to do. I want to touch on one other thing that is connected with this. You have been amazingly focused in putting together major works in nephrology. You just have to look around this room and you see "The Kidney" and other books. And we also know, I want to sort of comment on the information, the keeping the knowledge current and abreast for those in training and those in practice, those in teaching, those in research, and then the linkage that to the developing world. You and I have been in libraries; even in very prominent places where the resources weren’t there. There might be a total of 20 books of everything. 20 journals…one…….a few issues of one journal and a few issues of another over 15 years. So this is an important issue not only for us, but how to approach this, and our colleague Kim Solez has been very involved in this, how to approach this for the future, because this is one way that a library that is that sparse can jump a whole generation or two within a couple of years.

BB: The basic question is how can we globalize the knowledge base?

JD: Right.

BB: How can those sites that are not yet mature gain maturity by tapping into the worldwide web, by having resources that are not just on paper, but electronic? In fact, if you were to look at my own renal division where there are 40 faculty.

JD: Right.

BB: We received issues each month of Kidney International because every member gets it.

JD: Right.

BB: And every member gets JASN and every member gets everything else.

JD: Right.

BB: So we have enormous duplication, triplication what have you. How many do we need?

JD: That’s a good question.

BB: So what do we do with the extras? Well the ISN made a program, said you can make a check on your annual subscription, don’t send me my journal, sent it somewhere else. I don’t know how fully exploited that is?

JD: I think only a little bit.

BB: I think the big problem just as with equipment is gathering up these journals and shipping them. Its dead weight, its heavy weight. Better is to ship the content electronically, but that requires that you have receiving equipment, that everybody is on a website. Well website gives you more that just the ability to transfer knowledge, it allows you to have interchange. A physician with a complex case can wire transfer key features of the case to an expert in the developed world if need be. We can set up nodes how people proceed to get international opinions. We can view an x-ray, we can view a biopsy without having to peer down the microscope at the site that has the slide. So…

JD: This is something ISN should put as a high priority?

BB: Seems to me a wonderful challenge. Going to cost a lot of money to have the hardware and software distributed. Kim Solez has made an enormous dent in this problem. We went from nothing before him to something very substantial. I had correspondence with my colleges in nephrology in Cuba this week.

JD: Right.

BB: Well, made possible through equipment transfers that Kim Solez made, generated and I know this is true in many, many parts of the world.

JD: Yes, it’s made a huge difference.

BB: But we need more of that and so ISN to me as I look ahead; knowledge transfer, dialogue interchange, communication and prevention strategies using many parts of the world as unique laboratories. Again Cuba. You and I were there for a COMGAN meeting. Cuba has…unique in the world. 99.1% of the population has a personal physician.

JD: And records are kept.

BB: Well that’s a laboratory for clinical studies. It’s a laboratory for epidemiology of disease. What’s missing? Sufficient trained manpower and the funds to make the reality from the dream. It’s an island laboratory of unique proportions.

JD: Well I think that’s again a very good recommendation for ISN. Barry we’ve covered today, we’ve gone from when we were young, if I could say that, to and…

BB: To now when we are even younger.

JD: Younger and we still are mentally very, very, young and our bodies are still together. But we’ve gone a long way from basic science, came out of clinical residence programs and you’ve gone through a series of advances in clinical nephrology and taken to clinical trials. We’ve discussed the global issues. Now there are other aspects of nephrology that perhaps you want to make some observations on. You’ve headed a very dynamic, large, clinically intensive, and research intensive, and teaching intensive unit in Boston. Many trainees came out of that. They’ve populated many centers in this country and the world. You’ve had dialysis and transplant programs at hand. We’ve not discussed that issue and its maybe well discussed by many of the other people that the Legacy Program has interviewed, but I’m just leaving a few opportunities here for some other insights that you have accumulated over the last 40 years or so, same length of history as the ISN.

BB: Working at a wonderful institution like Brigham, like Harvard, allows more of the dream to be realized than might have been the case if I were elsewhere. We have enormous resources and the draw of these places as part of the finishing process in one’s education for people around the world is such that we’re blessed with 400 applicants for 10 positions each year.

JD: From all over.

BB: All over. All 400 are good enough to be here. Our problem is, like a kid in a candy store, you can’t have it all.

JD: Right.

BB: But we open our doors as much as possible. Arrange visits for three months, six months. Not everyone has to come for four years. The main training program is four years. Not everyone requires a salary. The home program can sponsor people. In some parts of the world people come with very substantial, personal means. The more we can accommodate the more we do accommodate, even though we have limited resources. But it’s a school and we run it as a school. We’re committed to the best that our school has to offer namely, come, be curious, work hard, take advantage of the opportunity and the rest will follow as you want it to follow in your dream. Make the effort; the rest will take care of itself. So I’m not surprised that I’ve got many graduates who have succeeded. They were blessed long before they got to us and we did nothing to diminish, if you will the promise that was there, but rather help it to blossom. And I’ve seen that over and over again and I make no distinction in the quality of our graduates between those who came from US schooling and those who came from schooling elsewhere.

JD: That’s a very notable comment and a remarkable achievement in educating those who have gone many places. Now Barry we’ve talked about what happened over the last 40 years and we’ve dwelled on the present situation, especially in global terms. It’s time to give you a little allowance to look into the crystal ball as it were where nephrology will be or could be in 2025 or in 2050? How do you see that as we pass this on to our successors and to our children and our grandchildren and everybody else?

BB: I don’t know. I can’t predict. I don’t have the gifts for that. Look I’ve been hoping that the Red Sox would win the World Series…

JD: Not since1918, that’s true.

BB: I’ve been in Boston for 26 years now I’ve been optimistic every April only to be depressed by October. But we have a new season and maybe this is the season.

JD: So far so good.

BB: What are the things about the past that might help us predict the future?

JD: Right.

BB: Because I do believe lessons learned are very relevant. Just as we use the record of the past in judging who we want to put in our program. We don’t know how any given person is going to turn out. So you take the evidence accumulated to date and say if the person who has accomplished these wonderful goals up to now, continues in an undistracted way with positive reinforcement and good mentoring, isn’t it likely that whatever that chemistry of success was is going to continue?

BB: I would say that’s true for our field. We’ve gone from the descriptive to the black box to some semblance of reductive science to now the genomics and soon having all of the proteomics worked out. In ten years all those things will be done. What will we do with the information? I say, take it back to the bedside. Find out what those genes are that make you susceptible and me resistant to kidney injury. Modify the expression of those genes if in fact they are modifiable. If maleness is a gene that causes you to have kidney disease and your sister not to have kidney disease, that’s not modifiable. You’re stuck with the fact that you’re the boy and she’s blessed that she’s a girl. But find those genes that connote susceptibility that you can do something about. So the physiological functions are modifiable. We can regulate them. The robustness of the inflammatory response we can modify all the way back to those genes that encode for the inflammatory mediators once we know what they are. We’ll be able, ultimately I’m absolutely sure, be able to put tissue from subject A to subject B, but know that in the recipient subject B the robustness of the immune response can be controlled by directing the therapeutic strategy, not at the last steps of the process, but at the genetic expression. It’s gonna come. So we’ll have risk stratification. We’ll know who’s at risk and who’s not. Then we need to know what the best ways to modify those at risk. That means the ACE inhibitor was the primitive end of the stream kind of thing. We’ll have a better drug that will modify the gene directly or suppress the gene itself. Not the expression of the gene, but the gene. We’ll then have treatments that are so rational that we’ll be able to talk in real terms about muting the biological response, the adverse biological response and that’s called treatment, but we’ll also be able to mute genes before they become expressed and that’ll be called prevention. Comes out of basic research, but we apply it back to the bedside. And the skills needed to do the latter are going to be those skills of epidemiology, biostatistics, clinical drug design, all of that stuff that you need part and parcel with the basic scientist. So we need an army of skilled workers dedicated to unearthing this new knowledge.

[So we’ve said what we’ve had to say.]

JD: Barry I’ve really enjoyed this conversation and I think we’ve covered a lot of ground and we’ve covered things in terms of the whole scenario from basic research to amazing clinical adaptations that I think will have long-term ramifications for the treatment of patients not only in our countries, but globally. I think it’s amazing what’s happened actually in so short of time. I also find your comments regarding the future not only very promising, but very optimistic. So I on behalf of the ISN I want to thank you and look forward to having another conversation like this in 10 years time.

BB: Thank you John. It’s been a pleasure sharing this couple of hours with you, discussing these issues of mutual interest. It’s a special honor for me to be recognized in this Legacy Series and I look forward to doing everything I can in the years ahead, as I’m sure you will, to seeing the rest of the experiment played out.

JD: We will indeed. Thank you very much.