Panel discussion and Q&A session IX: Nephrology

Prof. Tomasz Stompór, Prof. Jürgen Floege, Prof. Kamyar Kalantar-Zadeh, Prof. Alistair Ingram

Recorded at the 6th McMaster International Review Course in Internal Medicine.
All lectures available at the MIRCIM virtual platform, click here to buy access.

Professor Tomasz Stompór: Good morning, good afternoon, ladies and gentlemen. It's my pleasure to welcome all of you to the question and answer session for the set of fascinating lectures which were dedicated to the most interesting and the most important part of medicine, which is nephrology. This discussion and these lectures are a part of the MIRCIM 2021 Conference, which is [jointly] organized by McMaster University, the Polish Institute for Evidence-Based Medicine, the International Society of Internal Medicine, the European Federation of Internal Medicine, the university that I graduated from many years ago – which is Jagiellonian University, Medical College – and the editing house Medycyna Praktyczna. This congress is also endorsed by the American College of Physicians. I have the great pleasure of welcoming our speakers. The first lecture was delivered by Prof. Jürgen Floege, who is an eminent nephrologist, a very influential scientist, especially in the area of glomerular disease. He is also a co-author and co-editor of the renal bible, which is Johnson, Feehally, and Floege's “Comprehensive Clinical Nephrology.” I hope that Prof. Floege also remembers his trip to Poland in 2013, to a small village with a big castle, which is the region where I live. I hosted him at that time, when he received the title of an honorary member of the Polish Society of Nephrology. Welcome, Prof. Floege.

Professor Jürgen Floege: Welcome, thank you.

Tomasz Stompór: I also have the great pleasure to introduce our second speaker, who is Prof. Kamyar Kalantar-Zadeh, professor of medicine, pediatrics, public health, and nursing sciences and the Chief of the Division of Nephrology, Hypertension, and Kidney Transplantation at the University of California, [Irvine] School of Medicine. He is also the co-chair of World Kidney Day. I just want to remind all of you that World Kidney Day is an extremely important and successful initiative and [that] all nephrologists, every at the beginning of March, for many years have gathered together with patients, students, and doctors of other specialties to teach about how important kidney diseases are. Prof. Kalantar-Zadeh is also the President of the International Federation of Kidney Foundations and the World Kidney Alliance. It's a really great pleasure to have you with us today, Prof. Kalantar-Zadeh. And our third speaker is Prof. Alistaire Ingram, who is the Professor of Medicine at McMaster University and Saint Joseph Healthcare Hospital. And Prof. Ingram has been interested for many years in the issues of the treatment of patients with chronic kidney disease. This year he has been speaking about the very, very important topic of referral to nephrological care, including and with special attention on the issues of referral of older adults into renal care. And it was really, very important and I am sure many questions will be asked [about] this wonderful lecture. Today we unfortunately cannot meet Prof. Samira Farouk from Mount Sinai University in New York, in the United States, because of some personal, very important duties which arose just prior to our meeting. I just want to remind you that at the bottom of our tool – Zoom – you can see the question and answer icon and all the participants may ask the questions all the time and we will try to answer them as they arrive. Let me ask the first question to Prof. Floege: “You mentioned during your lecture that when you treat a patient with hyperkalemia, you should never use bicarbonate of calcium at the same time. I presume this is due to avoidance of precipitation and calcium carbonate formation.” Is that the proper answer? This is a question from our participant.

Jürgen Floege: Yes. One day when you have a minute, steal some bicarbonate from the ward and steal some calcium solution and put them together: you will get a beautiful milky stuff. So every nephrologist also knows, when you dialyze, you can never mix concentrated bicarbonate and calcium. It always has to come through two different lines. This is what…

Tomasz Stompór: Of course. It should be forbidden to mix them just within a single solution, but one may follow another, right? That is not a problem?

Jürgen Floege:Absolutely, absolutely. The problem is when you have highly concentrated calcium and highly concentrated bicarbonate. The moment it's dilute, it's not a problem. I mean, you and I don't crystalize.

Tomasz Stompór: Yes. As we know, patients even without such an infusion, have a lot of problems with calcification. So indeed, we should not help them this way [and] make this problem even bigger. There is another question…

Jürgen Floege: …resuscitation. I mean, there it doesn't matter. This is only good for a resuscitation situation. Don't play with it otherwise.

Tomasz Stompór: Yes. There is also another question; I think it's very, very interesting and important because you mentioned Kayexalate and sodium in Kayexalate – as for today, what we mostly use in the treatment of hyperkalemia is still Kayexalate because the new drugs are just about to be registered or [are] not really popular. So the question is whether the sodium which is provided with Kayexalate has any meaningful role in the patients' outcome. And “are there any consequences of sodium load?” This is maybe the first part of the question. And the second is, “are there any studies which suggest any objective role of Kayexalate in the treatment of patients?” Do we have any data that it saves people's lives?

Jürgen Floege: [Those are] 2 very good questions and 2 questions for which there is no good answer. Kayexalate has about 1.5 g of sodium per 15-g dose. So if you give it 3 times daily, you add almost 5 g of sodium. I'm not aware that anybody has systematically studied whether this has an impact, but every nephrologist should be concerned when you add 5 g of sodium to your daily sodium intake. So, that's question number 1. The other question is even harder to answer because, again, I'm not aware that anybody has ever studied long-term outcomes if you give Kayexalate or any other sodium polystyrene, sulfonate-based potassium binders. It's frequently done, there are concerns about intestinal obstruction – which appears to be dependent on sorbitol content – but I haven't personally seen it even though it's quite frequently used. But in most of my patients, I don't use it on a chronic, long-term basis.

Tomasz Stompór: Of course. By the way, do you think that the amount of sodium which is contained within Kayexalate may be the problem in… because you mentioned emergencies. One of the emergencies that you did not address – because of many reasons, of course, you could not address everything – but this is of course profound hyponatremia. So I wonder if the sodium content within Kayexalate may be the load which may be enough to correct sodium too quickly? If we [were to] imagine such a situation that we need to lower the potassium [level] in patients with, let's say, sodium, let's say 100…

Jürgen Floege: I can only imagine. I mean, first of all, most hyponatremia is due to fluid overload rather than full sodium loss. But if you correct that with oral sodium administration, I would assume – but this is more a gut feeling than knowledge – I would assume that the increase in serum sodium is relatively slow and safe.

Tomasz Stompór: Yes. Of course, if any of our other speakers have comments on the issues that [we] are touching on, you are very welcome to come to the discussion and [give] your own opinions.

Professor Kamyar Kalantar-Zadeh: If I could also add, the issue of sodium-based medication, especially potassium binders, is an ongoing discussion. And Kayexalate has been with us for over half a century, right? And this is the one that we have been using – when I was practicing in Germany it was the same, and then in the United States from New York to California. And the concern is always if the sodium component of this is an extra burden. And this problem has never been resolved for over half a century. So hopefully, Prof. Floege and others, under their leadership and changing the paradigm, hopefully I see that we moving to a different direction. But this is important, not just for nephrologists but for the entire medicine to see what to do with the sodium components of Kayexalate as well as medications similar to it.

Jürgen Floege: I mean, maybe there will be renewed interest in this issue, given the 2 new potassium binders that are entering the market. So, patiromer has no potassium in there, where sodium zirconium cyclosilicate is very similar to Kayexalate – it may be a little less sodium, but it's a significant amount. And that may ultimately spark renewed interest in this question. And I fully agree with Kamyar: it's amazing that we have been doing things for 50 years and nobody cares. They are telling us it must be reasonably safe, [] we don't kill patients.

Tomasz Stompór: Yes. We have… There was a question also asked previously and now we have another question on the same topic, but the issue is that you mentioned both new drugs – patiromer and sodium zirconium cyclosilicate – as potentially… I mean, to be used in life-threatening situations, emergencies. But the question is, our listener says that he doesn't think that these drugs were tested in an emergency model, that they were rather used in order to prevent hyperkalemia in those patients who are using ACE inhibitors or [], not really to lower potassium in an emergency situation. And at the same time, we also have the question on your opinion on Lokelma, a new drug which was introduced recently. So these questions, I think, can be combined. How would you like these questions? Can we consider those drugs as emergency drugs?

Jürgen Floege: Yes, another good question. Lokelma is probably not useful [for emergencies]. It hasn't been tested in the emergency situation but it probably makes no sense because the onset of the effect takes a minimum of 7 to 8 hours: it's too late in emergency situations. So for that purpose, sodium zirconium cyclosilicate, if it's ever licensed in Europe, may be more attractive. But you may as well use the old Kayexalate, which has an onset of effect in, depending on whether you give it orally or as an enema, about 2 to 6 hours. So in that respect, in emergency situations, I believe the 2 new potassium binders don't really add much. In addition, you have to see that at least Lokelma is some 40 times as expensive as the old Kayexalate.

Kamyar Kalantar-Zadeh: Could I also add that, as Prof. Floege astutely alluded to, there is going to be research or a re-emergence of the importance of potassium binders, especially now that we're pushing more for a plant-based and plant-dominant diet in CKD [chronic kidney disease]. For 2 or 3 decades we always said “don't eat…” to any patients with kidney disease; we recommended one of the worst things we could have ever imagined, telling them not to eat healthy food, right? So there is a new paradigm shift, out of that tradition, that is a more plant-based diet, and with that comes a concern of potassium load. Therefore, this kind of discussion is very relevant, about how the new armamentarium, the emerging medications, [can also] help these patients to take advantage of the important features of a plant-based diet that usually is expected to slow CKD progression and [is] also good for the cardiovascular profile, while not causing hyperkalemia.

Tomasz Stompór: Yes. OK. And we have another question for Prof. Floege. Although the NIH and Euro-Lupus approaches – this is for the next topic of his lecture, which is vasculitis and rapidly progressive glomerulonephritis – although the NIH and Euro-Lupus approaches are considered equal, based on the literature, the listener has a strong feeling that the NIH approach is more effective in severe cases. Can you comment on that?

Jürgen Floege: Yes, a good question. I mean, in the KDIGO guidelines, which will finally be published in October of this year in the “Kidney International Supplement,” we will recommend for lupus nephritis class III and IV a Euro-Lupus scheme, which is the lower dose where you give fixed doses of 500 mg [of] cyclophosphamide every 4 weeks and, if I remember correctly, it's given over 3 months. So, you have a significantly lower amount of cyclophosphamide compared to the older NIH scheme. And we have fairly good data from ANCA [anti-neutrophil cytoplasmic antibody] vasculitis that 10 years later that may translate into tumor risk. So malignancy is an issue. But I also agree with the listener that it depends on your patient. The Euro-Lupus scheme is called “Euro-Lupus” because it's mostly used in Caucasians and tested [in Europe]. So if you have, in particular, Black or Hispanic patients, who often have a much more aggressive lupus nephritis, you could certainly consider giving them more cyclophosphamide at the risk of having more adverse events, short-term and long-term.

Tomasz Stompór: OK. Thank you very much for this answer. And we have another [comment on] your lecture, Prof. Floege. First of all, … excuse me. Well, this is a question [about] your particular practice in Aachen. First of all, you are perfectly right with your Friday afternoon vasculitis referral, indeed it seems to be true. And the question concerns your particular experience in your institution in Aachen: “Is plasma exchange available 24 hours a day for 7 days outside the ICU and is it always available in the ICU?” I think that our listener must be impressed by the problem with implementing plasma exchange very soon after the patient's appearance. And I mean, this is also my experience. So how does it look in your institution in particular?

Jürgen Floege: Yes. I mean, you see my hospital in the back[ground] and we are very technical. So yes, indeed, I'm in the fortunate situation that I can have plasmapheresis 24/7. But, I believe there are very few indications where you really need it in the middle of the night and where you can't wait until early morning. I may be tempted to use it if I get a very severe case of thrombotic microangiopathy; then I might be tempted to use it in the middle of the night, but certainly not for Goodpasture [syndrome]. In ANCA vasculitis, we've just learned that it's probably not very helpful and we're still debating when to use it. So, in most indications I guess you can reasonably wait until the next morning. But if my patient comes in on a Friday afternoon – and literally, 80% do – and they have a condition requiring plasmapheresis, don't wait until Monday. You definitely want to start on the Saturday morning.

Tomasz Stompór: Thank you very much. And we have a question for Prof. Kalantar-Zadeh, which is as follows: “Thank you very much indeed for emphasizing the fact that the intake of 2.4 g of sodium per day is totally unrealistic, as the PURE study and everyday practice shows the usual intake is 2 to 3 times higher than that.” But the question itself is, “how would you explain the J-curve relationship between sodium intake and outcome in its lower end?” So in other words, what is the explanation for the potentially harmful impact of low sodium intake in patients which has been shown, for example, in the PURE observational study?

Kamyar Kalantar-Zadeh: Yes, actually sodium has an association with mortality, based on the observational studies – they are mostly observational, population-based [studies]. That means dietary sodium intake and mortality and the fact that the American Heart Association recommends a sodium intake of less than 2.3 g or even less than 1.7 g per day for those who have hypertension, which is very unrealistic in my opinion because… yes, I have patients who, sporadically, really try very hard and reach 2 g or lower. But then, observational data in the past 10 years, including papers of high credibility, published in the New England Journal of Medicine, in JAMA, The Lancet, all these things showing that once the intake of sodium goes below 2 g, mortality actually goes up, right? So there is a J-shaped, I would even all it a U-shaped association. And where is the sweet spot? We don't even know. To be fair, maybe the very low sodium and mortality association is because these are very sick patients and they are trying very hard to avoid high sodium, but we don't know if this avoidance of salt is also killing them, right? So we don't know. [This] is a question [that] remains unanswered. There is not going to be any clinical trial because, like in many other areas, this is where trials probably will never happen, and similar to the fact that we never randomize people to smoke or not smoke [in order] to see who dies and who gets lung cancer – this is another area. So I think that it's best to say, “avoid high sodium,” not to say “go extremely low.” Anything that's extreme is probably not physiologic. We tell our patients, if you don't have hypertension or edema, try not to eat more than 3.5 or 4 g. And if you have hypertension, try to go below 3 g if possible. Why? Because we emphasize other aspects of food, such as the source of protein being from plants, plant-dominant; we now say 50% [should come] from plants and the other 50% from non-plants. So in summary, yes, there is a J- or U-shape phenomenon which has been consistent, and I feel we will never find the correct answer because there will not be clinical trials.

Tomasz Stompór: Yes. Would you think that the overstimulation of the renin–angiotensin–aldosterone [system] in such a low sodium intake may be one of the reasons?

Kamyar Kalantar-Zadeh: Yes, actually some of these papers have done a great job in coming up with these hypotheses and discussions. One of them is as you, Prof. Stompór, astutely mentioned. About the renin–angiotensin–aldosterone system being over-modulated, which causes more harm than help, right? And then, probably we also have to look at the evolution of physiology – why [does] mankind have a craving toward salt? Probably, it's something related to survival, right? Of course, in this day and age salt is everywhere, so the craving causes more harm, but the craving doesn't mean that we go from one extreme to the other extreme. So there are so many great hypotheses and I think all of them have biologic plausibility.

Tomasz Stompór: Yes, thank you very much for this answer. I have, I would say, a little bit of a funny question, because you showed on your slide that dialysis patient who had just caught a fish. Can you comment on the impact of fish in the diet on the kidneys and the general outcome of patients with advanced CKD? Since fish in general are generally acknowledged as a healthy food, but, for example, they contain a high amount of phosphorus. So this is, of course, as you mentioned, the plant diet which will probably be very promising in the treatment of patients with advanced CKD, but fish are still considered healthy. What about fish and advanced CKD?

Kamyar Kalantar-Zadeh: Well, it's a good question. Again, I would like to also ask maybe Jürgen and Alistaire to contribute, since they are also nephrologists. So I am going to start first. In this so-called plant-dominant approach to the diet, where we also need studies – and this is where we need clinical trials because we can do clinical trials. The last one was MDRD [Modification of Diet in Renal Disease], back in the late '80s and published in 1994, so it's almost 30 years ago. And the MDRD was mostly based on the old notion of low protein but high biologic value, that means more meat, more red meat. Sadly, it was the component of that way of thinking at that time, that if you eat less protein, you need more meat. Or if you need [to lower] potassium, therefore we push them to eat more meat and red meat. So if you look at the plant-dominant – remember I don't say “plant-based,” I don't say “vegetarian” – plant-dominant is half from plants [and] the other half… as you said, Thomas, that is a good point, and then the patients ask me, “what should the other half be?” I say exactly what you said: mostly fish, if possible. Why? Because there are data, and if you also look at the DASH diet – because what we are [talking about], plant-dominant, is very similar to the DASH diet, but there are certain similarities and distinctions – so there are overwhelming data about the impact of fish oil related to CKD progression, but these are again observational data. They are very small randomized trials. And if you put them… the question is [] that DASH diet people did in Hopkins. We put together also the plant-dominant, 50% plants and the other 50% mostly from fish or, after fish, poultry – but try to avoid red meat if possible, to bring it close to 0, if possible. And then have different approaches like plant-dominant level 1 – 50% or 75% or the fish part being 20%, 30%. So I can hypothesize, but I'm here to tell you – especially in front of great colleagues as Jürgen and Alister – I can't make up data; I can just tell you there is no randomized trial. We need to team up to show that that works. And based on what you just said, that means the combination of plants and the non-plant [part] being mostly fish-based. We feel that it's biologically plausible to see improvement of CKD progression and improvement of [the] microbiome. And [additionally], if they are on ACE inhibitors and SGLT2 inhibitors… because I remember 30 years ago – ACE inhibitors [were] there, I was in Germany – they said “don't go to nephrology, there is no future in nephrology, there is a new medication called ACE inhibitor and nobody will ever have kidney failure.” Thirty years later, it hasn't happened. Now they are saying the same about SGLT2 inhibitors: They will remove kidney failure from the history of mankind. This will probably never happen. I don't know what other colleagues think.

Professor Alistaire Ingram: I just heard the same thing about SGLT2 inhibitors, funnily enough. Why go into this now, with SGLT2 inhibitors? Yes, I would agree: fish-based diet. Some fish are a little high in phosphorus, but who knows if that's important or not. But certainly fish and poultry much more so than red meat. Also in the salt discussion, I am reminded of the interesting observation about the native populations in the interior some of the Indonesian islands that have virtually salt-free diets and renins that are over 1000, 2000 and they have a very low rate of cardiovascular disease.

Tomasz Stompór: Yes. I think that [it's a] similar story with nuts because when you look at the composition of nuts, they are also high in phosphorus. They are plants, of course, but in all observational studies, including DASH, nuts always contributed to better outcomes, although apparently they are high-phosphate. My private theory is also that nuts are probably eaten by people at a higher socioeconomic level, and this may be a confounder, that this is not necessarily due to the dietary impact but it is [rather] a kind of confounder. [Although] it is high-phosphate, I think it's healthy.

Kamyar Kalantar-Zadeh: If I could also add to that?

Jürgen Floege: It's plant-derived phosphate, which is much more difficult to absorb than some of the phosphate additives; they are the most terrible. But maybe I can give a very brief story. I had this patient come to see me with IgA nephropathy, a GFR [glomerular filtration rate] of 25, youngish, so… dialysis coming, he was very nervous. And then – and I can highly recommend this to you – he married a Korean lady. And she changed his diet from a typical German schnitzel, you know, diet to a Korean diet. I saw this guy again about a year later and his GFR had increased from 25 to 35, which is I guess – and he hadn't lost muscle, so that was not the trivial explanation – but I think that's a beautiful example of how diet can help stabilize kidney disease, even at very low GFR levels, and maybe even gain a little back. And his proteinuria had almost decreased to 0.

Kamyar Kalantar-Zadeh: So Prof. Floege, if I could also add, as you said, phytates in the plants, are full of phosphorus. I mean, the core component of phytate is phosphorus, but it's less absorbable. So the viability of phytate, or plant-based phosphorus, is 10% to 20% or 30% – these are data not even coming from human medicine, [but] from veterinarian medicine – and then as compared to the phosphorus from animal-based protein, which is much higher absorbable by [00:31:47]. Also, even that – as Prof. Ingram astutely mentioned – fish has absorbable phosphorus, but we are not even sure in this day and age if … the benefits of fish [outweigh] the harm of hyperphosphatemia. And similar to the session we had about potassium: If we have effective potassium binders and phosphorus binders or phosphorus modulators, now with the new medications that are coming, we should give that freedom, I mean, they should allow our patients to eat more healthy, while controlling potassium and phosphorus effectively.

Tomasz Stompór: Especially given the fact that meat is also very phosphate-rich, so it doesn't make too much difference in fact.

Jürgen Floege: It depends where the meat is coming from. Once again, by far the worst is processed meat. If you compare regular chicken meat with a chicken McNugget, the phosphate content will almost double and the sodium content will almost double. So anything that's processed is a problem.

Tomasz Stompór: Exactly. And Prof. Kalantar-Zadeh, you just predicted the next question, which is [about] tenapanor, which decreases passive paracellular phosphate absorption in the gut and is about to be accepted for use. Do you think or believe that this drug will change the rules of nutrition in advanced CKD in the future? So this exactly addresses your statement from half a minute ago. How would you comment on that? Will it be a game-changer?

Kamyar Kalantar-Zadeh: Yes, that's a good question. I mean, we have had phosphorus binders for 30 plus years, officially under the name of phosphorus binder. And whether or not modulation of transcellular and paracellular phosphorus absorption could play a role… the answer, I would say, is theoretically yes, but as in many other things we have seen and discussed – like the ACE inhibitors, SGLT2, phosphorus binders, potassium binders – at the end of the day, what matters is a combination of medication and lifestyle change, right? So we are hoping… it's hypothesized that this phosphorus transport modulator could play an important role in combination with a phosphorus binder, right? And in combination also with healthy food, that means not to eat what Dr. Floege [mentioned], processed food, Coke or Pepsi. I mean, nothing against the brands Coke or Pepsi, but these are pure phosphorus; it's 100% absorbable phosphorus. Essentially you are drinking phosphorus. And I don't think there is any medication known to mankind that could absorb that amount of phosphorus, as the patient comes to the [00:34:58] and drinks Coke and Pepsi. I don't know, what do you think?

Tomasz Stompór: Yes. But what is your personal opinion in general?

Kamyar Kalantar-Zadeh: Jurgen, you are on mute.

Jürgen Floege: Maybe, Kamyar, one question on tenapanor. I have no experience with it, but my understanding is that the mode of action of tenapanor causes diarrhea because you lose sodium and water in the intestine. So you can't separate the mode of action from diarrhea. How much of a limitation will that be? Patients don't really like that.

Kamyar Kalantar-Zadeh: My patients actually, that's a good… I'm not against, I'm not here to deny that part of the side effects; that means more loose stool and diarrhea. But we have more patients with constipation with CKD.

Jürgen Floege: That's true.

Kamyar Kalantar-Zadeh: And in fact, if anything could help them… one of the reasons I push for a plant-based diet, is also more fiber; we didn't even touch base on the amount of fiber – or the anti-acidosis part – but the fiber part is good for the bowel movement. Because if bowel movement works slow, maybe the potassium burden issue – hyperkalemia – could also be resolved, right? And diarrhea also, as we know, causes hypophosphatemia by the way, so we don't know if eventually a medication causes less phosphorus because of the side effects of that, right? That's a good hypothesis.

Tomasz Stompór: Interesting. OK, so now we move to the lecture of Prof. Ingram, and the first question is as follows: “A couple of years ago, in 2011, the paper by [00:36:41] and colleagues was published in [00:36:46] medicine, in which the authors concluded that the referral to a nephrologist may actually be dangerous. Too much erythropoiesis-stimulating agents, too much vitamin D product, parathyroid hormone over-suppression, erythrogenic adynamic bone disease, too much iron, too early dialysis, and so on.” So the final question is, “where do we stand now? Have we improved our strategies and stopped overtreatment in general?” What is your point of view, Prof. Ingram?

Alistaire Ingram: So Wolfgang Winkelmayer published, about 10 to 15 years, ago a number of really lovely studies about early referral versus late referral, which wasn't exactly what my talk was about, but they're still lovely studies. And the study that the questioner refers to, I believe, was primarily looking at a population that I'm very interested in – which is the elderly, so people over the age of 65 – over a long period of time in 1995 to 2006, [with] early referral versus late referral, defined at 90 days. And really what they found was that especially as time went by, the later time was 2006, early referral to a nephrologist was associated with substantially higher hemoglobin. You can argue whether or not that could be harmful. But also substantially earlier initiation of dialysis, with a very, very small survival benefit, tiny, so like 0.6% or something like that. I would argue that with an early initiation of dialysis – and the GFR, I think, was 50% higher [in those who] saw a nephrologist earlier – these are older individuals, [so] you would expect the bigger survival benefit just by lead-time bias. So I think there is reason to be apprehensive about early referral, particularly of older Individuals. But you know, as long as we are focusing on starting dialysis appropriately, not based on numbers but rather on, you know, symptoms or hopefully symptoms starting to [00:38:59], you know, we should be able to overcome a fair bit of that. But certainly, it does raise some concerns and, you know, one needs to bear this in mind.

Tomasz Stompór: Well, I think that the guidelines have been changed quite substantially concerning CKD-MBD and anemia targets. So I hope that this landscape has changed because we are much, much, I would say, [less] aggressive I would say in general, right? So we now realize how overtreatment may harm our patients.

Alistaire Ingram: Yes. The story of nephrology between ACE inhibitors and SGLT2 inhibitors has been primarily one of good trials telling us to do less.

Tomasz Stompór: Right. So, this is a question which is actually very, very tightly associated with our previous discussion because the question is, “do you believe SGLT2 inhibitors will become a game-changer on nephroprotection in non-diabetic CKD and will they change the landscape of CKD in the population dimension?” I fully agree that they will not eliminate CKD as a disease, as Prof. Kamyar Kalantar-Zadeh mentioned before. That's totally impossible. But the question is, “would you expect any population effect, that there will be a visible decrease in the progression of GFR in the population dimension?” That's a very interesting question, I think.

Alistaire Ingram: Yes, so, I mean, SGLT2 inhibitors are really pretty exciting, I have to say. And I am kind of old and a bit of a cynic, but I think they're pretty exciting. I mean, so far, you know, [there's only been] 1 published trial where we're specifically looking at non-diabetics or a good proportion of the trial registrants were non-diabetics in DAPA-CKD. And we await the EMPA-KIDNEY trial. But you know, you've got to like the results between DAPA-CKD and CREDENCE, the other studies. It is all pretty substantial risk reduction, you know? it's all pretty synchronous. So I think it's a real thing, you know, in my practice I am certainly getting patients in those GFR bounds and with proteinuria onto these drugs. And I hope that with EMPA-KIDNEY, maybe we can lower that GFR a bit and get more patients onto these drugs, but I do think it's a real thing.

Tomasz Stompór: Thank you very much. I agree with that. OK, and there is another question for Prof. Ingram, because you focused in your lecture on when to refer – or maybe not to refer in some cases – patients with established advanced CKD and you also shared some experience from Canada and from your region. But the question is, in the view of the listener, the most important challenge in his or her opinion is how to identify patients with apparently asymptomatic active glomerular disease, for example, non-nephrotic proteinuria. And what is your experience on that? [Are there any], let's say, screening programs or early detection of active glomerulopathy, because I also agree that this is… I don't know what is the opinion of Prof. Floege, Prof. Kalantar-Zadeh, how to… are there any, I don't know, holy grails to identify those people who would suffer later on with chronic kidney disease because of undetected glomerular nephritis? How can it be done?

Alistaire Ingram: So, I am interested to hear what my colleagues have to say on this too. I would look at this a couple of ways. So the question referred to non-nephrotic proteinuria and, for sure, I mean, it's difficult to diagnose a glomerular disease just on the basis of the presence of proteinuria. I wouldn't get too worried about non-nephrotic proteinuria because most of the glomerular diseases that we think of that present primarily proteinuria, you are not going to rush into treatment if they've got non-nephrotic proteinuria anyway. So you would just be doing things like you would be doing for anybody with CKD. I would find… just from the practical point of view, I get a little more worried about things like ANCA or lupus. I do see a few patients who are pretty asymptomatic outside the kidneys with ANCA or lupus. So you know, when you a patient with proteinuria and you also have some hematuria, that certainly gets my hackles up a bit more. And you know, I order a fair bit of ANCA and ANA [tests] in the office. But in terms of these patients with proteinuria, the ones we're going to treat are going to be symptomatic for the most part, right? They are going to have nephrotic syndrome, they'll have edema, there will be some other clues that there's a problem there.

Tomasz Stompór: Any other comments on this topic?

Kamyar Kalantar-Zadeh: If I could ask, as Dr. Ingram said, first of all we need to make sure that symptoms of the patients are not missed. That's very important. And that's also for the treatment of patients with nephrotic syndrome or other things. And also when we start… thinking about starting dialysis, we start patients on dialysis on a gradual basis, only once or twice weekly. This is now starting in California a model, which has been quite established here. This is what we don't ever, I mean I can't say that we don't ever start somebody on twice weekly, it's twice weekly. Now going backwards through time, when somebody has nephrotic syndrome or even mild proteinuria, I invariably tell them that no matter how many great medications I give you, I still would like you to lower the amount of protein [you eat], less than 1 g or less than 0.8 g per day, and focus on more a plant-based diet. As Dr. Floege said, there are stories like this. These are anecdotal stories also, of course. He said that somebody was eating a lot of German food and switched to Korean, vegetarian food and things improved. There are a lot of those stories, but we don't publish them because sometimes they cause credibility issues. We would like to be data-driven. So I would again emphasize [that] no matter how many great medications we give to these patients, we need to make sure that the diet and lifestyle is also adjusted, not to tell them “go and eat whatever you want” – including for proteinuria. That means I have seen proteinuria going all the way [to] 50% lower or more, sometimes with the same medications, the same SGLT2 and ACE inhibitors a patient is taking. And the moment the patient says, “doctor, I decided not to eat meat” and the proteinuria goes from 3 g to less than a gram. So I would like to encourage colleagues to give it a shot, to try it and see what happens.

Jürgen Floege: The other thing to watch out for is two-fold. Smoking: if you smoke and you have, let's say, IgA nephropathy, your risk to reach dialysis increases tenfold. It's massive. And what I've learned the hard way is – and I really talk to my patients for quite some time about lifestyle – what I've learned the hard way is… fitness studios. If you go into one of these torture machines and you lift 50 kg, 60 kg, and you know what guys do… you have incredible blood pressure peaks when you do that. Avoiding that and going to a more endurance exercise is a fantastic way of stabilizing kidney disease.

Tomasz Stompór: Very important comment.

Jürgen Floege: It's very simple measures. And you really have to talk to your patients. And I am amazed what I find. The latest anecdote is a Swedish guy who had high proteinuria with IgA nephropathy and I [asked] him: “Do you smoke?” “No, I don't smoke.” And then he mentioned something called snus. Do you know that in Poland? Snus is chewing tobacco that you put in your cheek pocket. And I told him, “hey, you have to stop this immediately.” His wife now loves me because it must be terrible stuff. And see, his proteinuria got down.

Tomasz Stompór: It's chewing of tobacco, right? A kind of chewing tobacco.

Jürgen Floege: You put it in your cheek pocket up there and it sits there the whole day … never kiss this person. So is this why the wife was so happy when I said, “hey, stop it.”

Tomasz Stompór: Oh my God. Thank you very much for these comments. And we have just a thanks to Prof. Ingram: someone wrote, “I really love your statement on the precious time left for older adults that should not be wasted in the queue to a nephrologist.” I think that all of us fully agree with that statement. And we have a question also to our colleague who is absent, Prof. Samira Farouk. But I think we could try to answer it all together because this is a question on a very hot topic. Hopefully, it won't be COVID-19, but the question is [about] post-COVID-19. So what is your prediction? And I address this question to all of you because you have experience from different countries, different parts of the world – from Europe, from Germany, from Canada, and the United States. What is your prediction concerning the post-COVID-19 era in nephrology? Do you think that renal post-COVID-19 syndrome will exist? Who should be monitored and how after survival of COVID-19 in terms of renal follow-up? It's quite a multi-level question, but what are your opinions on this? What will happen, let's presume that the COVID-19 pandemic will stop. But what should be our attitude, our approaches to monitoring patients for the long-term consequences for the kidneys? Can we somehow answer that question? Please, Prof. Floege.

Jürgen Floege: Well, if I may start, my take-home message from the literature so far is that AKI happens in COVID-19, but if you compare it to other very sick patients, it's neither more common nor more severe nor more deadly. AKI affects many patients on the ICU and we should follow all of these in the long term to see whether they have a restitution back to normal or whether they have persistent CKD. I don't really see any particular COVID-19 syndrome that I have to follow as a nephrologist. I would wish we would follow all AKI in the long term.

Tomasz Stompór: Yes. Prof. Kalantar-Zadeh?

Kamyar Kalantar-Zadeh: Yes. So back in January, 4 months ago, 5 months ago, we had a major surge in southern California. Our hospital, my entire hospital became an ICU. And then we used clinic buildings for regular beds. And then we put a tent outside, so it was a bad month. And I was interviewed [and] I called this a war zone; I saw things that I had never seen. We ran out of dialysis machines; we ran out of dialysis nurses, because they also got COVID-19; we ran out of nephrologists; a few of our fellows got COVID-19 and one of them was in the ICU. And the number of CRRTs [continuous renal replacement therapy] we were doing, usually it's 3 to 5 CRRTs a day – we went to 15 a day. And we ran out of machines. I had to make decisions [about] who today gets to survive one more day and who doesn't. So it was a tough time. And I'm not sure if this [number of] AKIs that we saw and we ran out of dialysis machines was because the COVID-19 denominator was high or COVID-19 causes, kidney disease. We published an editorial in Nephron about… we put together data showing that COVID-19 goes to the kidneys and data showing that COVID-19 does not go to the kidneys, right? So there are both sides, you have a good number of papers on both sides, but one thing is for sure. As Dr. Floege said, when you have sepsis, you also have AKI, right? These patients were dying and, at the end, many of them needed dialysis whether or not we see now post-COVID CKD – but that also is another thing that happens with AKI, right? When you have AKI, you have residual AKI in the form of CKD in many of these patients. So it's so many unanswered questions, but I am so happy that we survived. It was a bad month for us in January 2021; I will never forget what happened to us. And I hope none of you guys ever undergo and experience what we had here.

Alistaire Ingram: We've had nothing like that near-death experience you guys had in southern California. We had our fingers crossed for you guys down there in the early part of this year. It was terrible. When we first started seeing COVID-19… I mean McMaster is a big hematology place, so everybody got very excited and ginned up about the thrombosis business. And so you know, as nephrologists, we were a bit concerned [about whether we'd] see prolonged AKI or non-recovery AKI as a consequence of intrarenal thrombosis. And I would agree with Dr. Floege, I mean, so far that has not panned out; they've kind of behaved like other AKIs. Maybe we shouldn't be surprised that there is at least one biopsy study showing that when you biopsy people with sepsis in the ICU – I don't know how they managed to do this – you see quite a lot of intrarenal thrombosis. So maybe we shouldn't have been surprised. You know, I'm busy setting up post-COVID-19 clinics for the hospital now. From the medicine point of view, it's primarily a lung and – to a lesser extent – an autonomic neuropathy phenomenon. Those are the people who seem to be getting into longer-term problems. The people we've had with AKI who have survived their ICU experience have all recovered.

Tomasz Stompór: But do you think that, let's say, the problem of people who were not referred and [left] untreated over the period of the pandemic would be the issue? Because my personal experience is that patients now are coming with really, let's say, advanced medical problems, including advanced kidney disease, which was not detected due to telemedicine, due to limitations with access to general practitioners [and] specialized centers. Is it also your experience? Because this is something that I can see.

Alistaire Ingram: I think we probably should get Dr. Kalantar-Zadeh to comment on that. I am not seeing that, but we did not have the same type of COVID-19 here.

Tomasz Stompór: Dr. Kalantar-Zadeh, you have your… Yes, now it's OK.

Kamyar Kalantar-Zadeh: Yes, as I said, these are all unknowns, this is uncharted territory and I think we will see as the field develops. We have to wait and see.

Tomasz Stompór: OK. And Prof. Floege, any other comments on that?

Jürgen Floege: No, sorry, I actually I am afraid I have to leave [in] a few minutes. Thank you all. Bye, bye.

Tomasz Stompór: OK. But, fortunately – thank you very much – but fortunately we are almost out of time. We are about to finish. So there are no more questions in our… Oh, there is also another question whether the COVID-19 AKI is predominantly a glomerular or tubular disease? Well, I presume that [in most] cases this would be… [problem with connection]. …at least different glomerular involvements also in COVID-19. So this is of course probably a mixed issue. Ladies and gentlemen, it is my great pleasure to summarize the session. We had an opportunity to meet on the question and answer session eminent nephrologists from all over the world. They were Prof. Jürgen Floege from Germany, Prof. Kamyar Kalantar-Zadeh from California, United States, and Prof. Alistaire Ingram from Canada, from McMaster University – which is one of the co-organizing institutions of this wonderful congress. Thank you very much to all the participants, to our great speakers. And I hope we will have the opportunity to meet at the next occasion during the next MIRCIM congress. Thank you very much.

Alistaire Ingram: Thank you. Take care. Bye.

Kamyar Kalantar-Zadeh: Thank you. Bye.

Co-financed by the Polish Ministry of Education and Science within the program „Doskonała Nauka”
(„Excellent Science”)

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