nephSAP Guest Editor Interview: "Hypernatremia"
ASN Podcast
Published July 17, 2026 * 00:27:10
Martina McGrath, MBChB, FASN; Jean Francis, MD, FASN; Ihab Michel Wahba, MD, FASN; and Amir Kazory, MD, FASN, speak with guest editor Biff F. Palmer, MD, to discuss his editorial on Hypernatremia from nephSAP Volume 25, Number 1.
Please note that this transcript was automatically generated and may contain inaccuracies. It is intended for informational purposes only. Refer to the audio for full context.
----Speaker 1: Welcome, everyone, and thank you very much for joining our NEFSAP podcast today, which relates to our acid-base issue of NEFSAP. I am delighted and honored today to be joined by Dr. Biff Palmer, who is a professor of education and internal medicine at the Texas Health Science Center in El Paso, Texas. He's been a tenured professor of internal medicine at UT Southwestern for many years and remains an adjunct professor there and continues to serve in an educational capacity. Many of you will be very aware that Dr. Palmer is deeply steeped in nephrology research and education. He has authored more than 300 articles. He's been a program director for the Renal Fellowship Program at UT Southwestern and has several editorial board activities. He has quite an extensive CV with a long number of teaching awards, but those that are most notable, he's been awarded the Burton Rose Endowed Lectureship and also received the Robert G. Nerins Award for substantial and meritorious contributions in education and teaching. And Dr. Palmer, we are thrilled to have you here today and we're delighted to have your contribution to our upcoming NEFSAP issue. Thank you so much.
Speaker 2: Thank you very much. It's a true honor to be able to participate in the NEFSAP project. It's been around. It was, as you know, started, I think, by Dr. Nerens. And I know it's been a publication well received by the readership, for sure.
Speaker 1: Thank you. I'm also joined today by the other members of the NEFSAP team. We've got Dr. Ehab Waba, who's a professor of medicine at the University of Pennsylvania. Dr. Amir Khazori, who's a Professor of Medicine at the University of Florida, and Dr. Jean Francis, who's also a Professor of Medicine and Medical Director of Kidney Transplantation at Boston University Medical Center. So our team today are delighted to have a chat with you. I'll start off a little bit, Dr. Palmer. And one question that I think many of us kind of fastidious nephrologists often raise, and when we're rounding with how staff and trainees in particular, you raised it in your article, this whole question of volume depletion versus dehydration, I think is a central issue when we think about hypernatremia.
Speaker 2: Absolutely. Yeah, you know, it's kind of a semantic thing, but I've always told the house staff, when you're talking about, or when you utilize the word dehydration, by definition, you're really referring to somebody with hypernatremia. It implies a water deficit. And when you use the term overhydration, that means a relative water excess. And I think it's important to distinguish that from the term volume depletion or volume overloaded, where you're really referring to the total body sodium content. And that's a parameter that you can assess by virtue of physical exam and selective tests like urine sodium excretion, the fractional excretion of sodium, and those kinds of things. So I think it is important to be, you know, specific when we use those terms, hydration status versus volume status.
Speaker 1: And that obviously impacts how we care for those patients too.
Speaker 2: Absolutely. I mean, when you're talking about volume disturbances, yeah, I mean, we're either talking about the administration of salt or using diuretics, whereas hydration status disorders, we're obviously focusing on water content, either water overload or water deficits.
Speaker 1: One of the points that I think is increasingly recognized as we care for patients in hypernatremia is this high rate of mortality that's associated with hypernatremia. Could you talk to us a little bit about what we know about that?
Speaker 2: Yeah, you know, it's somewhat similar to hyponatremia in the sense that, you know, a drop in the serum sodium or a rise in the serum sodium seem to be at least associated with the worse outcomes. I mean, one can certainly make the argument that it may not necessarily be a direct cause and effect. Obviously, individuals who get hypernatremic are those that have not been drinking, oftentimes because they're obtunded, they can't get up and go get water. And so maybe by virtue of their underlying diseases, that's what's really driving the mortality. Nevertheless, I think it certainly is a useful marker and it's been borne out in numerous epidemiologic studies that a high serum sodium, really in a graded fashion, is tightly linked to worse outcomes.
Speaker 1: I think as well, when we see it develop in the hospitalization and in the ICU, it's frequently a marker that our patients are just not doing well.
Speaker 2: Absolutely.
Speaker 1: One comment you raise as well is the the effect of potassium balance in the management of hyperkalemia, I think we're, sorry, of hypernatremia. We think about it a lot in terms of hyponatremia, but perhaps less so when we care for patients with hypernatremia.
Speaker 2: Yeah, absolutely. You know, I think, and hopefully so, most people are aware that, as you allude to, when When you're hyponatremic and hypokalemic, just simply replacing the potassium deficit will cause an increase in your extracellular sodium concentration. In other words, as we administer potassium to a potassium depleted individual, as potassium moves into the cell, it's gonna obligate water movement into the cell as well because of the increase in intracellular solute content. And that has arguably much more important implications in the management of hyponatremia because it can certainly cause sometimes a dramatic rise in the extracellular sodium concentration. The same thing will occur, I mean, in somebody who's already hypernatremic, I mean, the serum sodium might rise further, but I guess in terms of therapeutic outcomes, it doesn't have the dire consequences as with, for example, rapid correction of hyponatremia. So it's just a predictable physiologic effect of replenishing a potassium deficit, but maybe clinicians aren't, you know, as aware as they should be. But that's one of the things that I thought was important to bring out in the manuscript.
Speaker 1: Great, thank you. You also talked a little bit about this whole concept of bound and osmotically active sodium, where we have sodium loading and tissues and the implications and thinking about total body sodium and management of these patients. Can you explain to us a little bit the background physiology there?
Speaker 2: Yeah, so as you know, that's a story that's been now out for a number of years that is, There seems to be a discordance between the total body salt content within an individual and the actual amount of sodium that's osmotically active. There's obviously evidence that sodium can be retained in a quote-unquote non-osmotic form in lymphatics, in the subcutaneous tissue. And sometimes, particularly in experimental studies, there could be a disconnect between measurable total body sodium content and what's actually measured in the extracellular fluid compartment. And that disconnect is, again, what's confined to these tissues. And I think, you know, we continue to understand maybe that has some clinical relevance, for example, hypertension, for example, you know, increases in total body sodium, some of which is not readily measurable, these tissue potassium stores may actually be ideologically related to phenomena like poorly controlled hypertension and the like. And so again, I think it's an evolving story, but nevertheless, one that is gaining a lot more appreciation. I remember, for example, even, for example, SGLT2 inhibitors, there was a paper, I don't have the reference right on the top of my head, but it talked about the benefit of SGLT2 inhibitors actually reducing some of this tissue sodium content. And so I think people are really looking into this variable as it pertains to sodium disorders.
Speaker 1: I guess, are there any particular, it's a little off topic maybe, but are there any particular groups of patients that are more susceptible to this kind of total body sodium loading? Obviously the hypertensives, but are there particular groups even within that where we see that more frequently?
Speaker 2: I mean that the hypertensive individual is the one that comes to mind, but maybe it also applies to people with heart failure. Yeah, I'm not sure if I know the answer to that. Maybe that's an area that's worth exploring further.
Speaker 1: Yeah, it's a very interesting thought given the difficulty with controlling hypertension and I guess the high salt diet that so many of our patients are taking.
Speaker 2: Yeah.
Speaker 1: Going back to your paper a little bit more, and you had a very nice section on diabetes insipidus, and one that particularly caught my eye were some of the autoimmune causes of diabetes insipidus. You mentioned a little bit about DI induced by the checkpoint inhibitors that we're seeing more frequently.
Speaker 2: Yeah, I mean, obviously, these biologics have really revolutionized the therapy of cancers, and the outcomes are just really tremendous with some of these biologics. But these programmed cell death ligand modulators induce, in essence, an autoimmune reaction to certain excret organs. And one of the things that's been well described is endocrine abnormalities resulting from an autoimmune reaction to the hypothalamus, the pituitary gland. Now, probably the more common manifestations of that are cortisol deficiency, things like that. But in addition, there have been occasional reports of a central diabetes insipidus brought about by this lymphocytic infiltration into the hypothalamic structures. And so it's just something to think about. If one did have an oncologic patient who started having polyuria, polydipsia, you know, probably the most common thing we'd think about in that setting would be hypercalcemia, maybe drug-induced hypokalemia. But this, in the absence of any other identifiable cause, I think we at least need to think about this autoimmune reaction brought about by these biologics. Kind of a... A spin-off of that too is one of the other things I discussed in the paper is just somebody de novo presenting as a central DI. There are rare reports now of patients who have developed antibodies against the sodium channels in the hypothalamic structures. and that there's an autoimmune-induced central DI due to specific antibodies against these sodium channels that are thought to be involved in modulating the extracellular osmolality and its regulation of vasopressin. And so that's quite fascinating. Probably not common, but nevertheless, something to be thinking about.
Speaker 1: Fantastic. Thank you very much. I'm going to open this up to the rest of the team if anyone has any other questions. Please, Dr. Waba, go ahead.
Speaker 2: I had a question regarding the management of hypernatremia in hospitalized patients. We often see, not often, but occasionally we see the hypernatremic patient who's in the ICU, perhaps not able to drink water in the setting of the management of congestive heart failure or ARDS. What do you think about replacing the water deficit in this setting and what should we tell our cardiology and critical care colleagues about that? To be sure, I didn't get so much into the therapy in this article, just simply for space constraints. But, you know, I do think that, well, first of all, I think we always need to primarily focus on hemodynamics. So I always tell the house staff, stabilize hemodynamics. That's your number one priority. And then worry about the tonicity disorder. So if somebody were total body salt overloaded and not really able to tolerate additional fluids, you're going to be a little bit more judicious in administering free water. I mean, to be sure, only one-twelfth of water stays within the circulating compartment. But nevertheless, it can be. be something to think about in somebody who has borderline cardiac function, if you will. But nevertheless, we don't want to ignore the hypernatremic subject. So I think slow, gentle hydration with D5W can be done. But again, I think you have to pay attention to the overall hemodynamics as your number one priority. With regards, the one thing that's, I think, true about hypernatremia is we don't really have to worry about overcorrecting it. By that, I mean, you have to purposely overcorrect hypernatremia, whereas hyponatremia, as soon as you shut off endogenous nasal pressing, the kidney has this massive ability to clear a water load. On the other hand, truly rapidly correct hypernatremia and then develop secondary cerebral edema from that, you almost have to purposely do that. So in that sense, I think we're a little bit protected. And there's actually been a couple of reports. I didn't get into this in the article, but there's been some publications looking at rates of correction of hypernatremia. And it seems that the frequency of adverse events is pretty low. So unlike the clinical the clinical issue with hyponatremia, it's not the same with hypernatremia. I'm not sure if the rest, if my colleagues here would have any differing opinion on that, but that's my impression of this literature.
Speaker 3: Thank you, Dr. Palmer. You know, great conversation. I have two questions. You described that the brain has this tolerance to tolerate a broad range of hypernatremia because it can generate some osmolyte into the neurons, which could drag water back into the neurons and protect them. Would those, their presence, would it affect how fast you correct hypernatremia or you still don't worry about this prolonged hypernatremia that generated those osmolytes? Would they affect your judgment and how fast you correct or you don't? We shouldn't worry about that.
Speaker 2: No, I mean, it's a great question, and you're exactly right. I mean, so the cellular adaptation to this high extracellular tonicity state is the increase in intracellular osmosis, a variety of amino acids, certain alcohols like myo and inositol, and specific amino acids like betaine. These have all been described as so-called non-perturbing osmoles that allow the cell to maintain its shape and size despite the large increase in extracellular osmolality. Again, my reading of the literature is, yes, theoretically, if you were to rapidly lower the extracellular sodium concentration, the potential side effect would be cerebral edema because of the high cell solute content. But when you've actually looked at the data, where clinicians have described rates of correction, the frequency with which you see these adverse events is, again, not as high as I think we always would encounter with rapid correction of hyponatremia. So I'm not arguing that we should ignore it, but really, if you think about it, if you were to... In order to accomplish rapid correction of hypernatremia, you actually have to iatrogenically pound the patient, if you will, with a lot of free water. It's almost like you purposely have to do it. And I think most of the people, most clinicians probably never accomplish a rapid correction because you can go through the calculations and say, this is the amount of water deficit. but you're always a little bit behind because of ongoing free water losses. So again, I think it's just kind of a hard thing to bring about, but we don't want to ignore it, but I think we've got a lot of room for errors on that side of the serum sodium concentration versus hyponatremia, where there's a lot less room for error because of the kidney's rapid ability to clear water loads.
Speaker 3: And one more question, was the increased use of SGLT2 inhibitors and their glucosuria and osmotic diuresis. We're not seeing too much hypernatremia, and I think people drink water, but are they at higher risk of hypernatremia compared to non-SGLT-2 treated people if they have no access to water? Should we alert the clinician about this potential? Like, is this something like you tell your patients?
Speaker 2: Yeah, I mean, theoretically, I think you're exactly right. You do induce, obviously, a natriuresis and an osmotic diuretic effect, if you will, from the glycosuria. And so you would think that hypernatemia would be a potential side effect. It's obviously not common because most people who are taking these drugs have an intact thirst mechanism. To support your question, though, as you well know, there's actually a couple of papers that have actually looked at SGLT2 inhibitors as a way to manage chronic hyponatremia as a way to get more water loss. So I don't think we're seeing hypernatremia as a common complication because people who are taking these drugs are intact, but it is a theoretical modality that could make things worse were it to be present. Yeah, that's a great point to bring out.
Speaker 4: Thank you very much. Actually, following up on the question that Dr. Francis had, so patients in your paper, patients with ADIPSIC or hypodipsic, hypernatremia central DI, many of them may have the urine osmolality that might be super high despite hypernatremia. And I was thinking, how would that happen? If I have high urine osmolality, then why do I still have hypernatremia? This is actually because we had a patient. Apparently, the hypernatremia will start if you lose your thirst or you are behind with free water. Otherwise, the AVP can be just not present or you can have lower AVP levels and not yet get the hypernatremia. Is that right?
Speaker 2: Yeah. So, you know, that's initially patient population. So the term has been adipsic hypernatremia. implying that there are individuals who have both abnormalities in the thirst mechanism and also a suboptimal, not complete absence, but suboptimal release of the vasopressin. And as I point out, if you look at some of these papers, because obviously this is a fairly chronic condition, You encounter patients who may have quite strikingly elevated serum sodium concentrations, but yet be very clinically intact with minimal to no manifestations, so... Again, I think the fact that they're maintaining these high serum sodium concentration implies that the thirst mechanism is much more, there's definitely an abnormality in the thirst. If I understand your point, and I think you would have to agree, you know, even in the complete absence of vasopressin, the drive for water intake when it's available is quite strong. And that's why we see these people who have central or nephrogenic DI who typically have fairly well-preserved sodiums because they're just drinking all the time. So this unique population that you bring out are just representative of this close anatomic relationship between where the thirst center resides and the centers that release vasopressin reside. And so there are individuals who can have manifestations of deficiencies in both processes. And that makes sense because they're so close anatomically. I guess that would be my only comment there. Perfect. Yeah, the only thing, you know, I guess you could have all the vasopressin you would want in the world, but yet the serum sodium will rise if you're not drinking. I always tell the house staff, there's only, I'm only aware of one source of water that could be endogenously, if you will, generated within the body. And that is with starvation. As you deplete glycogen stores, it is said that you release as much as a liter of water into the body, that there is stored water in glycogen. And as you deplete glycogen, you actually, it's almost like a camel effect, you provide endogenous water. This is actually my, what I have provided as an explanation for why, for marathon runners who get hyponatremic and yet lost no weight during the race, why in the world would they be hyponatremic? And I would argue that if they depleted their glycosid stores, released this compound of water to explain why they got hyponatremic with no water loss. or no body weight reduction.
Speaker 4: That is very interesting.
Speaker 2: Very interesting.
Speaker 3: Dr. Palmer, your description, how the volume stimulus to ADH always overtake the osmotic state, even in the hypovolumic state or hypervolumic. I didn't know about the hypervolumic state. That's fascinating. Like you need to reset to a higher sodium to stimulate ADH, as you were explaining.
Speaker 2: Yeah, and I'm sure you're alluding to, for example, hyperaldosteronism, right? Yes, exactly. The serum sodium concentration is typically 144, 145. It's almost as if... the volume expanded state is suppressing the release of vasopressin, requiring a greater rise in plasma osmolality till you now reach a new steady state. And you're exactly right. It's kind of the opposite of hyponatremia where you have heart failure, you have cirrhotic patients who are Hyponatremic, and yet vasopressin is still elevated, driven by the low effective volume. Yeah. I always say that this overriding effect of volume to stimulate vasopressin likely is teleologically related to other effects of vasopressin. Remember, vasopressin stimulates the von Willebrand factor. It's procoagulant. It obviously at very high concentrations exerts vasoconstriction. And yeah, it causes water. Now, water's not a great volume expander. Only 1/12 stays in the vascular tree. But if you're hemorrhaging, it might make sense to release a compound that retains water, vasoconstricts, and is a pro-coagulant. It could be a vestige of our Paleolithic ancestors who were attacked by a woolly mammoth. Exactly.
Speaker 3: And you need the volume, like as much as you can retain of it to survive. You don't want the sodium being low to shut the vasopressin release. You want the volume to control it or overrule it.
Speaker 2: Absolutely, absolutely.
Speaker 1: Wonderful. Fantastic. Well, Dr. Palmer, thank you very much. This has been a really fascinating discussion and really very enjoyable. Thank you so much for your time, and thank you again for your contribution to NEFSAP.
Speaker 2: Well, thank you again, and I'm very grateful to the editorial board for allowing me this opportunity. Thank you very much.
Speaker 3: It's a pleasure.
Speaker 1: Thank you, everyone.
Speaker 5: This podcast is copyrighted by the American Society of Nephrology. All rights reserved. All content in this podcast is for informational purposes only and is not intended to be medical advice. This podcast should not be used in a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or another qualified health care professional if you have any questions about any medical conditions or before or taking any drug, changing your diet, or commencing or discontinuing any course of treatment. Thank you for listening to this podcast by the American Society of Nephrology. I'm Todd Ibrahim, Executive Vice President of ASN. If you're a nephrologist, fellow, or kidney health professional looking to advance your career, stay informed, and build connections, I encourage you to become an ASN member. Membership, which is free to fellows and other trainees, offers exclusive access to groundbreaking research through our journals, discounts to live and virtual educational programs, including Kidney Week, in support of a global network of nearly 22,000 kidney professionals. To learn more or join ASN, visit www..asn-online.org.
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Episode URL: https://www.asn-online.org/media/podcast.aspx?ID=669