CME-MOC

Amboss Article on Hyponatremia

Time Stamps

Show Notes

Pearl 1 – General Approach

  • Hyponatremia is a significant clinical problem:
    • Most common electrolyte disorder, occurring in up to 30% of hospitalized patients
    • Mild chronic hyponatremia is associated with more frequent falls – gait and attention impairments have also been observed
  •  H&P – may be helpful, but don’t ignore other objective data that contradicts!
    • History: 
      • Quickly assess for red flags (confusion, seizures) → immediate intervention, ICU admission
      • Ask about dietary history, fluid/EtOH intake, new meds, endocrine ROS, relevant comorbidities
    • Physical Examination:
      •  Volume status is theoretically helpful as diagnostic algorithms hinge on it, but error prone
  • Our approach focuses on understanding what each diagnostic test adds vs. rote dependence on algorithm
    • More helpful given that most hyponatremia in the hospital is multifactorial
    • Ask yourself where your patient with hyponatremia is on “Cartesian space” with:
      • Anti-diuretic Hormone (ADH) secretion, as indirectly measured by UOsm relative to
      • Effective arterial blood volume (EABV), as estimated based on clinical examination and measurement of urine sodium
  • What if we encounter a patient after intervention, and without complete labs or urine studies? 
    • Still obtain appropriate serum and urine studies as you can assess response to interventions (urine output, change in urine concentration and serum sodium) and the patient’s current ADH/EABV state 

Pearl 2 – Serum Osmolality (Normal value 280-285 mOsm/kg)

  • We expect patients with true hyponatremia to have a low osmolality (<280 mOsm/kg)
    • This makes sense because sodium is the most significant contributor to osmolality
      • SOsm= 2 [Na+] + [Glu]/18 + [BUN]/2.8
      • The equation in countries that use the metric system also entails sodium x 2
  • Serum osmolality can be thought of as a “quality check” to rule out other osmoles that may be contributing to the hyponatremia. 
    • If osmolality is normal assess if the patient has high triglycerides or an extra protein in blood (e.g. Multiple myeloma, recent IVIG administrationSuch cases referred to as “pseudohyponatremia” = lab artifact, not of clinical significance.
      • Computer expects that aqueous component of blood is 93%, with 7% serum particles
        • High serum lipids or extra protein changes this ratio and impact the sodium calculation
        • Want to be sure? Whole blood sample of serum osmolality will not be subject to this error
        • Such cases referred to as “pseudohyponatremia” – laboratory artifact
    • If osmolality is elevated (usually >280-285 mOsm/kg), or if normal osmolality without elevated proteins/lipids, look for extra osmoles, either measured or unmeasured!
  • Serum osmolality assessment prompts us to consider effective and ineffective osmoles at play:
    • Effective osmoles (sodium, glucose, potassium) do not cross the plasma membrane, and therefore cause shifts in water movement  (impact tonicity)
      • Most of the clinical complications that arise as a result of hyponatremia (and its correction) are driven by the fact that sodium is an effective osmole – it impacts tonicity, and therefore cell size. 
    • Ineffective osmoles (ethanol, urea, lactate) cross the plasma membrane more readily, and therefore do not cause shifts in water movement (does not change tonicity) 
  • Serum osmolality is not a serially measured lab! 
    • Measure it once unless there is a significant sodium change that is difficult to contextualize. 

Pearl 3 – Urine Osmolality is a window into ADH activity

  • Urine osmolality (UOsm) is the nearest window into ADH activity as we have in clinical practice (although copeptin has promise as a surrogate for ADH activity)
    • Range of possible urine osmolality in healthy kidneys is broad (50-1200 mOsm/kg) 
      • ADH secretion stimulates resorption of free water in collecting duct, resulting in high urine Osm
      • ADH suppression results in low urine Osm
  •  If ADH is not active in context of hyponatremia, dilute urine results (UOsm <100-200 mOsm/kg). Low urine osmolality on presentation is indicative of:
    • Too little solute with normal fluid intake (tea-toast syndrome)  
    • Too much fluid despite normal solute intake (primary polydipsia)
    • Some combination of low solute and high intake of hypo-osmolar fluid (beer potomania)
    • Can also occur in the setting of acute illness, where patients will take in large volumes of hypotonic fluids (i.e. sports drinks) in the setting of poor po intake and ongoing GI losses
  • The story of hyponatremia is often the story of ADH activity;
    • One study found that non-osmotic ADH release is present in 97% of patients with hyponatremia!
    • ADH activity is reflected by UOsm >200-300 in patients with hyponatremia
      • If ADH is present, the next step is to figure out whether because of decreased EABV, increased osmolality, or independent of physiologic stimulus (see pearl 4 below)
  • Remember that renal insufficiency impacts our ability to maximally dilute urine and maximally concentrate urine
    • Hyponatremia may develop as a result of acute or chronic renal failure for this reason
    • Renal insufficiency limits our ability to interpret UOsm as a direct window into ADH activity
  • Change in UOsm (and urine output) can be assessed serially to determine response to treatment
    • If urine osmolality decreases with your intervention (e.g volume resuscitation), this indicates that your intervention has resulted in suppression of ADH (proving your hypothesis)
    • Heads up! If urine output and UOsm change dramatically in response to an intervention, this may be an early indicator a patient is correcting too quickly

Pearl 4 – Urine sodium, FeNa, FeUrea reveal RAAS activity

  • UOsm gives us a window into ADH activity at a given time – it does not tell us why ADH is activated. 
    •  Physiologic or “appropriate” ADH activity can occur in the following circumstances:
      • Hyperosmolarity (readily apparent when serum Osm >285 mOsm/kg)
      • Low sensed effective arterial blood volume (may be hypovolemic or hypervolemic, such as cirrhosis or heart failure)
    • ADH activity that is not stimulated by low sensed effective arterial blood volume (or hyperosmolarity) is by definition inappropriate
  • Urine sodium is a window into activity of renin-angiotensin-aldosterone activity
    • UNa <20 indicates the RAAS is active due to low EABV  (true hypovolemic or sensed hypovolemia)  
    • UNa >30 indicates no RAAS activation
  • In a patient with hypotonic hyponatremia, with elevated UOsm (ADH-driven hyponatremia)
    • A low urine sodium (UNa <20) and high urine Osm indicates low EABV
      • Either from true hypovolemia or sensed low EABV (e/g cirrhosis, heart failure)
    • A high urine sodium (especially UNa >30) and a high urine Osm indicates inappropriate ADH secretion
      • To understand why this is “inappropriate,” one must understand that in low EABV, RAAS is activated first and then ADH is activated 
        • It takes ~10-15% volume loss before ADH is activated
      • So, a high urine sodium indicates that RAAS is NOT on, which means sensed blood volume is just fine. Therefore, ADH secretion (indicated from high urine Osm) is “inappropriate”
        • Consider Syndrome of Inappropriate ADH (SIADH), adrenal insufficiency, hypothyroidism
  •  In patients with intermediate UNa (20-30 mEq/L) 
  • Caveats to UNa & FeNa use
    • Use of diuretics (thiazide or loop) increases UNa
      • FeUrea <55% is a reasonable surrogate in the case of diuretic use 
    • CKD impairs Na reabsorption, making UNa less helpful in this population
    • UNa will be low in patients with low Na diets (rare in US)

   Pearl 5 – A low serum uric acid can helpful when considering SIADH (in order words, point away from hypovolemic states)

  • The lower the serum uric acid level, the theory that the patient’s hyponatremia is less likely to be driven by low-EABV mediated ADH release
    • Sodium and uric acid reabsorption are coupled in the proximal tubule
      • EABV contraction will cause urinary sodium and uric acid retention (e.g low urine sodium and low urine uric acid)
      • EABV expansion (thought process with SIADH) will cause sodium and uric acid wasting (e.g high urine sodium, high urine uric acid).
  • Expected characteristics of uric acid in SIADH:
    • Serum uric acid → low (<4 mg/dL)
    • Urine uric acid → high
    • FeUricAcid →  high >12%
  • FeUricAcid may be a more helpful diagnostic test when trying to distinguish between causes of hyponatremia with low EABV and normal/elevated EABV
    • [(UricAcid (Urine) x Cr (Serum) / UricAcid (Serum) x Cr (Urine)]  x 100
    • Patients with saline-responsive hyponatremia (increase Na by 5 mmol/L with 2L NS) have significantly lower FeUricAcid compared with saline non-responders (P<0.01), usually approximately 4%

Transcript

S: Hi Everyone! The Core IM episode this month will count for CME credit with the ACP – we will link the URL in the show notes, so follow the link, complete the 3 questions and get CME credit. Without further ado, cue the intro!

Jeffrey: It’s funny, because even when we’re called – and I’m sure you guys have had this experience – where the nephrology team is following that hyponatremic patient with you and like day 3 comes and the sodium’s the same. And everybody’s like, “Oh, you know, we’re doing our best, but hyponatremia is complicated!”

S: That’s Dr. Jeffrey William, a nephrologist at Beth Israel Deaconess Medical Center and I just SO appreciative hearing even a very smart nephrologist say that hyponatremia is complicated! 

M: Yes – hyponatremia IS complicated, but we’ll try to demystify that a little today. Welcome to the Core IM 5 Pearls Podcast. This is Dr. Marty Fried, a primary care physician at THE Ohio State University Wexner Medical Center.

S: This is Dr. Shreya Trivedi, an internist at THE Beth Israel Deaconess Medical Center.

M: Wow Shreya – let me tell you Buckeye nation reallllly doesn’t appreciate it when you steal their “the” Shrey.  

S: How can i not poke fun a that?! Also, joining us today is Dr. Tim Rowe, currently a chief resident at THE University of Wisconsin Madison. Marty – did you want to say it this time?

M: GO BADGERS! Thanks, Shreya, it’s been awhile. Love Madison. Love Tim. Love Lamp. Boy are we glad to have you here today, Tim. 

T: Hey!! Thanks for having me guys … it’s great to be back! 

S: And also, thank you to our friends at Amboss, which is also a medical education platform for all levels! We worked behind the scenes with the team to create this episode!

M: Yes, big shout out to Amboss. They have a ton of easy to use content on things ranging the spectrum from drug dosing, radiology imaging, even management checklists.

S: If you’re looking for something more comprehensive on hyponatremia, we did work on an AMBOSS article on hyponatremia, linked in our show notes. They’re also offering a free trial on their Knowledge app for something quick and easy at your fingertips.

M: And today we are going to start the first of a two part series on hyponatremia with diagnostics! Especially because with hyponatremia, we usually rely on that same old tired algorithm.

John: I find that that algorithm that I was bequeathed by my residents when I was a med student about how, okay, first you figure out the volume status, then you figure out if it’s ADH or not… it implicitly suggests that there is one etiology that is driving the hyponatremia and I have found again from experience consistently, that is almost always never the case.

S: Core IM listeners might recognize the voice of our very own Dr. John Hwang, Belleuve Hospitalist and of course co-host of our “Hoofbeats” segment on Core IM. 

M: And so today we wanted to break down hyponatremia a little differently by moving beyond rote memorization of that algorithm 

S: And instead thinking about what tests you are ordering and  how they can help us describe what is happening to our patient physiologically. 

M: So that the next time you’re admitting a patient with unexplained hyponatremia, we want you to think of these tests like your four buddies, each with their own purpose and personality… like “The Beatles” of hyponatremia.  

S: No no no… I kind of hyponatremia labs as The Avengers! Come nik fury is serum osm.. Iron man is urine osm.

M: Alright, alright – what about Houses of Hogwarts?  The Channel 4 News Team?  The A-team – I can do this all day!  And with the look that Shreya is giving me right now I think we should get started on the questions we’ll be covering today. Test yourself by pausing after each of the five questions.  

S: Remember – the more you test yourself, the deeper your learning gains!

M:  Pearl 1 – General diagnostic approach

  • What are common pitfalls in the general approach to hyponatremia?

Pearl 2 – Serum osmolality

  • What does serum osmolality tell you?

Pearl 3 – Urine osmolality

  • What does urine osmolality tell you and how can you use it to help understand if your intervention is working?

Pearl 4 – Urine sodium 

  • What does urine sodium or urine urea tell you about causes of hyponatremia? Are fractional excretions of sodium or urea useful? 

Pearl 5 – Uric acid

  • How can we use serum and urine uric acid levels in the diagnosis of hyponatremia?

Pearl 1 – General Approach

S: Okay Tim, start us off with a case?

T: You got it, Shreya. You’re in the ED seeing Ms. Dee dee Hayveepee, who was just hospitalized for pneumonia. Her PCP sent her to the ED for a low sodium of 126 on her follow-up labs. She is feeling much better since her discharge, and notes that her cough and shortness of breath have totally resolved. You quickly check to make sure she hasn’t had any severe hyponatremia symptoms like confusion or seizures. But what should you do next?

M: I don’t know about you guys, but I’m looking back in her chart and hoping that her sodium has been low like this for ages. If she’s been cruising along with a sodium of 130 for the past 5 years, we’re golden, right?!  

S: Well yes and no! That chronicity has quite a bit of implications. Hyponatremia that’s not acute is independently associated with gait disturbances, cognitive deficits and a higher mortality rate in a lot diseases – so if it hasn’t been worked up before or if there is something we can do improve it, it’s def worth looking into.

M: Ok, yeah, fair, I guess when I do see one of my patients in clinic with hyponatremia, I pause, cry a little on the inside and pop open that damn uptodate page again… but, like all things internal medicine the workup really starts with a good history, right? 

Jeffrey: Yeah. The history is helpful when it’s helpful. But you know, when it seems to go at odds with the numbers you’re seeing, it’s hard to know which one to go with. Obviously objective measurements are objective and history is important, but subjective – you weren’t there, you didn’t see it when it happened.

T: Yeah, I don’t know about you guys but I’ve definitely been burned when my patient gives me this classic history that just does NOT jive with the objective data.

John: This case that sticks with me from a couple of years ago. Her sodium was in the low 120s, I think, on presentation. And, uh, she gave the admitting residents overnight a history of nausea, poor PO intake and vomiting.

T: Okay, I know I’m gonna regret it but this history has me locked and loaded on hypovolemia. Let’s crack open a few liters of saline, right guys?! 

John: She ended up getting a fair amount of intravenous fluid. And by the time I came onto the case in the morning, the repeat basic was already in progress. And when it came back, it was 116 and she ended up going to the MICU.

M: Oh dear that is unfortunate… so yeah talk to your patient buuuuttt be ready for new data that might change your mind.  

T: Yes! Stay open minded. We can also get tripped up by the physical exam. As good as we think our exam skills are, the reality is that clinical assessment correctly identifies hypovolemia and normovolemia only about half the time. That’s like a coin flip…but – you know – a crappy one. 

S: So it seems like the history and volume exam are more like hypothesis generating-activity, and really it’s the diagnostic tests which can help  to prove or disprove our hypothesis.

T: Yes! And speaking of diagnostics, let me tell you all about my hyponatremia nightmare. It’s when I walk in the room to admit a patient with hyponatremia, only to see a bag of normal saline already hanging, and urine a-pouring into the foley bag, and all of this before any of the additional labs could be drawn! And my ED buddy is like “Well, he looked a little bit dry to me.” And I’m like, “Noo!! How do I obtain my precious data?!

M: Urine a-pouring? Am I the only one getting 12-days of Christmas vibes here?  (singing) Saline-a-hanging, urine a-pouring and five confused medicine residents. 

T: Hehehe…very confused. Residents, attendings, the whole team!! But seriously, should I even bother checking labs after fluids are given?

Jeffrey: Yes. You should check all of it anyway. My feeling is this like this isn’t a disaster, right? I’m so appreciative of my emergency medicine colleagues thinking about how to fix hyponatremia. As long as the risk is lower than the benefit I think is worthwhile. It really shouldn’t have a huge effect on your workup. If they made it better fantastic, you’ve made a diagnosis… hypovolemic, and if they haven’t made it better then there’s something still to think about.

M: Yeah, and as a primary care doc I am a big fan of the old “diagnosis by therapy strategy”.  A patient’s response to treatment can be a hugely important diagnostic tool. 

S: Truth, but my hyponatremia pet peeve is when someone justifies not getting any hyponatremia labs because they got fluids in the ED! My soapbox is if the patient is still hyponatremic, you can still get a snapshot of what’s keeping their sodium low   with serum and urine studies. 

John: Certainly I am better served by approaching it as a question of, can I diagnose the state? You know, what is … basically someone is hyponatremic because there are certain leavers in the body that are causing this person to be hyponatremic. In other words, to have an excess of water relative to salt, what is the position of those leavers? What is sustaining this person’s state? That’s what we’re trying to understand.

S: So wherever you start the process – whether its when the patient first hits the door or whether it’s after 2 days of inpatient care hoping the sodium is going to trend in the right direction – how should we be approaching hyponatremia?   

John: Mentally, I’m trying to understand where they are, uh, you know, on two axes that if thought of together, you know, comprise the Cartesian space. So on one axis is the ADH level. And then the other axis is what is the patient’s intravascular kind of volume status. The reason why I try to encourage my residents to think about it this way is to reinforce the idea that you’re not searching for a single etiology, you’re trying to understand the state of the system, you know, the patient’s hyponatremic I get it, why are they still this way?

T: I’ve gotta own up and admit that I had to quickly google “Cartesian space” there – that one’s just not in my everyday lexicon. But basically we’re talking about a two-dimensional coordinate system with ADH secretion on one axis, and effective blood volume on the other. 

S: We explicitly want to bring up this approach at the start of the episode because it hammers home that in the real world, every patient may have several different contributors to the hyponatremia – even if on the surface it seems like the patient are in the same “bucket” in the algorithm as the patient next door with hyponatremia. And its going to be these diagnostics test that will help us understand the degree to which that ADH and effective arterial volume are playing a factor. 

T: Aaaaand that’s where we’ll leave it for now – but don’t worry, we’re going to spend plenty of time explaining this concept very soon. 

M: Ok let’s wrap up pearl 1. With respect to the hyponatremia history and physical, even the most compelling stories can be limiting or potentially misleading. 

T: Instead of the intimidating Uptodate algorithm we find it useful to think about hyponatremia workup within this “Cartesian space” of ADH (on one axis) relative to effective blood volume (on the other), especially because the etiology of hyponatremia is often multifactorial, and a searching for a single algorithmic endpoint for clinically significant hyponatremia is often fool’s gold.

Pearl 2 – Serum Osmolality

M: Boom, alright bring us back with the case, Tim!

T: Okay, so you’ve got a low sodium reading, now what? The hospital you’re working in reports a calculated osmolality with the BMP, and this comes back low at  267 – remember, normal value is 285-295, so 267 is solidly below that lower limit of normal – and you add-on a measured serum osm to confirm your calculated value. 

M: I’m not 100% sure which friend metaphor we’re using, but let’s say serum osmolality is your pikachu – not necessarily the best but usually the first pokemon you start the game with.

T: Alright, alright… yeah I think I see where you are getting with that, even if it’s clearly squirtle – I actually think of serum Osms like Alfred, you know Batman’s butler? He isn’t always in the thick of the things, but he’s the one who helps smooth things over for the ole ‘caped crusader’, and you definitely wouldn’t want to ignore what he was telling you.

S: Regardless of what metaphor we’re using, you definitely don’t want to ignore that serum osmolality is gonna be your quality check, its gonna tell you if its true hypotonic hyponatremia- in most cases of hyponatremia, we expect serum osmolality  to be low. But guys I felt like I’ve always memorized “okay, low serum osms, then real hyponatremia” but lets channel a little physiology Tony Breu -why do we expect osmolality to be low? 

M: I’m a big fan of channeling my inner Tony Breu but unfortunately, to answer that question we need to go back to that haunting serum osmolality equation.  

T: Yeah, so sodium is the largest component of that equation – remember, it’s two times the concentration of sodium, added to a fraction of the glucose and urea concentrations.

M: So sodium is making up the lion’s share of the osmoles in the extracellular space, and if the patient’s lab value of sodium is low then we expect the measured serum osmolality to also be low.

Jeffrey: If it’s not low, then it’s either isosmotic or hyperosmotic. And if it’s isoosmotic or hyperosmotic, you know that something else is contributing to that elevated osmolality, because that’s certainly not the sodium. And that’s what keys you in. As you go along, you can rule out these other things like hypertriglyceridemia or hyperproteinemia, or in some examples where you can detect a myeloma or some other cancer where there was extra immunoglobulins.

M:  And just to punctuate that – if you see low serum osmolarity you’re golden, pass go and collect your $200 on your way to determining etiology of “true” hyponatremia. Now, if you see a normal or elevated serum osmolality, you have some work to do.

T: That’s right Marty… but the first thing you’ve probably done, maybe without even thinking about it is glance at the BMP. If BUN or glucose are significantly elevated, boom! – there’s our answer. 

S: Yeah, if its not one of the obvious osmoles from the BMP, ask your patient about other commonly encountered osms like alcohol, or if you have found yourself wandering around a MSKAP question – you might look for those toxic alcohols like methanol (and calculate an osmolar gap)  

M: Oh dear, that is treacherous territory we are approaching.  What else should we be thinking about? 

T:  So when the serum osmolality is normal, we should also think about“pseudohyponatremia”. You probably all remember this nuisance, which is really just a lab error…. So if the serum osms are normal, check a lipid level for elevated triglycerides, and look for a protein gap to consider paraproteinemias like multiple myeloma or it even could be extra proteins that we give, like IVIG. Any of those might be the cause of pseudohyponatremia.

M: oooooh IVIG, good one Dr. House. Ok, here’s where things can get a little fun. And by fun I mean tricky. And by tricky I mean infuriating… 

S: Yeah what’s perplexes about the osmolality is when I get back lets say a normal serum osmolality in a patient who I believe has true hyponatremia and I get frustrated because the algorithm tells me it can’t be true hyponatremia if the osmolality is normal.  

T: The algorithm is lying. Your frustration is so valid, Shreya. Think about a situation where you’ve got a patient with real hypotonic hyponatremia from beer potomania… but they’re also acutely intoxicated with alcohol. Right?? Then the patient’s osmolality might  be normal even though he truly does have hypotonic hyponatremia. 

M: Right, so big teaching point here was that normal or high serum osmolality does not rule out that a real hyponatremia may be going on, just clues us in there are other osmoles around like ethanol in the case Tim just mentioned and there could be multiple things at play. Sort of like when you have a microcytic anemia AND a macrocytic process going on resulting in overall normal MCV. So don’t be tricked with a ‘normal’ serum osm – we expect serum osmolality to be low! 

S: We will link a table in the show notes that has all the extra osmoles to watch out for and which osmoles actually change tonicity, which dictates where free water goes.

M: Yeah def check that out for reinforcement! So, let’s talk about a rookie move thats often made with ordering a serum osmolality.

Jeffrey: Yes. But only check it once, please. We get consulted on patients with hyponatremia, and there’s a daily serum osmolality. You don’t need to do that. Once you are confirming that the serum osmolality reflects that of the serum sodium, you’re done! You don’t need to be checking it every day to say, “Yup! It’s still two times the serum sodium.” 

S: Yep guilty, I’ve definitely been on one of those teams that checked serum osmolality q8 hours with all the other hyponatremia lab, and but now that I know that serum osm is just helping me rule out thet there aren’t other osmoles or offenders messing up the sodium, im kind of embarrassed we were checking it so often. 

T: Nothing to be embarrassed about! But take away is, you only usually need to check the serum osmolality once, and again only if you think something new and funky is messing with your sodium.

M: And with that, let’s summarize pearl 2 on serum osmolality. Since sodium is our largest osmole, we expect hyponatremic patients to have significantly low serum osmolality. We check it, once, to verify this is the case. If serum osm is not low, we have some work to do. If serum osmolality is normal…. pop on over to the chemistry tab to see there is a protein gap or check a lipid panel looking for triglycerides that might causing lab artifact – this is pseudohyponatremia. Other things to think about if serum osms are normal OR high are things like hyperglycemia, alcohol or elevated BUN.  And remember that true hyponatremia can co-exist with extra osmoles, so normal serum osmolality doesn’t mean you don’t also have a real hyponatremia.  

Pearl 3 – Urine Osmolarity

T: Alright – back in the Emergency Department where you’re still conducting the most dramatic step-by-step hyponatremia evaluation in recent memory, your measured serum osmolality comes back low at 268, lining up with the calculated value and confirming your suspicion of true hypoosmolar hyponatremia. 

S: At this point, we have to go back to drilled into us from day 1 about hyponatremia.

Jeffrey: I make them stand up, I make them shout it from the rafters: “Hyponatremia is a water problem”.

T: Everyone, repeat after Dr. William… 

Jeffrey: “Hyponatremia is a water problem”

S: So we have to figure out where that excess free water is coming from that is driving down that sodium number. 

M: And to understand where free water may be coming from, we have to understand what is happening with ADH. And if we want to get at ADH activity, which friend are we reaching for now? 

Jeffrey: For me, it’s urine osmolality in hyponatremia – that’s where the money is.

S: So CLEARLY URINE OSMOLALITY is the Iron Man of hyponatremia labs! 

M: Yeah I mean urine osmolarity is the hyponatremia test of all tests. It’s your Dorothy of Oz, Beyonce of Destiny’s Child… Vinny of the Entourage crew.  

S: Right, and this is because UOsm is our window into what is happening with ADH in the body.  

John: If I was trying to explain ADH to like a first year med student, I would basically say ADH makes your kidneys retain water. And the corollary to that is it makes you pee out a very concentrated urine.

M: So what that means is when ADH is on, free water is being reabsorbed back into the body, leaving solute in the urine without water, making a spicy meatball… if you know what I mean. 

T: So basically the urine osm comes back high, you know ADH is on.

M: Right and on the flip side, if ADH is off, free water is being peed out, giving your patient dilute urine and the urine osms is less than 100-20.

T: So if the urine osm comes back low, ADH is off, right? 

S: Right. But we want you to remember that for the sake of this podcast we are using ADH on and off to make it simpler to wrap our brains around because in reality, it’s not a binary thing.

John: Thinking about in terms of not just is the ADH low or is it high, but rather how high is the ADH? How bad is it? Is it like 400, which is just modest or is it like 1200. 

T: In other words, you want to ask yourself where is your patient on the ADH axis? 

S: Is the UOsm really low, less than 50 and so, ADH is maximally suppressed or is the UOSM really high, close to 1200 and ADH is maximally on?

M: There is a caveat to this urine osm range is in our patients with CKD. With kidney disease, there is a much narrower range for what we consider high and low urine osms 

John: Renal insufficiency tends to compromise both the kidneys ability to dilute urine and its ability to concentrate urine. So, whereas a healthy person’s kidney ought to in response to hyponatremia dilute the urine down to like 50 or 75 and in response to hypernatremia, concentrate the urine up to like 1200. But, in someone with CKD, I know that that range is going to constrict. If they have CKD, then the most dilute, excuse me, the most, yeah. The most dilute that they might be able to make their urine might not be 50. It might well be 200 or 250. So that’s, I think that’s how the presence of CKD affects my interpretation of the urine OSMS.

M: So with that foundation –  lets dive deeper into what urine osm means clinically. In the vast majority of cases, the story of hyponatremia is the story of ADH being on.  

T: BUT there are very few cases where ADH is NOT the driver of hyponatremia (and not the driver for excess free water in the body). We’re talking about cases that have high volume, low solute states.

S: There are a few cases that give Uosm is going to low <100-200 because ADH maximally suppressed. You want to think about these scenarios: when someone is taking in too little solute to eliminate free water (M: tea/toast), overwhelming amount of volume intake (T: primary polydipsia), or some combination of the two (M: beer potomania) 

T:  I don’t know why but I used to think that tea & toast syndrome is rare…  but what I learned is that it can actually be kinda common and also under-recognized.  

Jeffrey: I’m not surprised anymore, but I’m often struck by when patients feel unwell, what they do to make themselves feel better. They revert back to this primal instinct – and I don’t know, or how it was inculcated in all of us – that we should be drinking lots of water. 

S: And one protip is to not just ask about drinking water but ask about all types of drinks our patients may be consuming when they are feeling crummy.

Jeffrey: They may make themselves feel better by saying, “Oh, I wasn’t drinking water, I was drinking Gatorade, or something else.” That actually wasn’t isotonic enough to give them more volume, but it was just simply a little bit less hypotonic than water. Any sports drink is just not going to have enough in the way of nutrients to get you volume replete, if you’ve become volume depleted. Any sports drink is not Pedialyte. You’ll know if you drink Pedialyte, it tastes different than a sports drink – it is salty, because it’s an oral rehydration solution.

S: And so you can imagine someone with a decreased GFR who isn’t able to get rid of their free water as well and feeling ill and chugging a ton of fluids, that can quickly lead to hyponatremia and if we were to check urine osms in these situations it may very well be on the lower end, which for CKD patients may be 200s or so as Dr. Huang alluded to.

What does Uosm >100 tell about ADH?

M: Beautiful so that was low urine osms! Let’s pivot to situations when your hyponatremic patient has a more concentrated urine – typically urine osmolality > 300. What does that tell you about ADH? Especially at this point when we’ve confirmed that Tim’s ER patient Ms. Vasopression or whatever does in fact have hypo-osmolar hyponatremia with a low serum osmolality.  

John: When you meet somebody who’s hyponatremic and you see that their ADH is in fact elevated and they’re producing a concentrated urine, there’s really only two possibilities. Either the body has chosen to sacrifice water homeostasis, osmolar homeostasis to defend something even more important, i.e volume status or intravascular filling, or there is something totally independent of that, that is causing the ADH to be high. And it could be something endocrinologic or it could be the SIADH or kind of what have you that’s those are really, I think the two buckets.

S: What John saying when you get back high urine osms, you know ADH is activated – and once we know that we have to decide if it’s in response to low effective blood volume or is it being secreted independent of that stimulus, one of which is the infamous syndrome of inappropriate ADH.  

M: Hold onto this because our pearl 4 buddy is urine sodium, and that rambunctious little fella going to help us figure out if that ADH is appropriate or inappropriate.  

Uosm can be used as a response to your intervention

S: Yes, there’s a lot more to unpack urine osmolality — it has MORE uses than just giving us a window into ADH activity at a given moment. 

T: Yeah the real reason Urine osms is my personal fav is because you can ACTUALLY use it to see if your intervention is working in real time! 

M: Like, say for example, you think you’re dealing with a correctable cause of hyponatremia, like hypovolemia. If you’re right then giving your patient fluids will cause the urine osmolality to decrease, reflecting that ADH turning off.

Jeffrey: So each day, if I’m measuring a urine osmolality and I’m watching it go from 700 to 500 to 300 to 150, I know that person is doing the right thing by their hyponatremia and they’re going to get better. If it’s not getting better, despite giving liter after liter after liter of fluids, because you think they’re hypovolemic – guess what? They’re not hypovolemic! If they were, their ADH would shut off and they would correct themselves.

S: For the longest time I honestly didn’t know what to do with urine osm we were getting q6hours for patients with hyponatremia. I didn’t know I could compare it to be what the urine osm was pre-fluids or diuretics and see if my intervention was working.

M: If we’re on the right track the urine osms will decrease over time, because as ADH is turning off, free water won’t be reabsorbed back into the body, and we should start seeing all that free water being peed out making crystal clear urine with a LOW urine osmolality.

Role of foley — peeing out a lot/clear/dilute urine = correcting cause

S: This is all fine and dandy when we are actually able to collect urine on our patients but I remember having a patient where it was really tough collect urine and someone just said oh, just look at the urine but never understood why or what it was telling me.

T: I love looking at the urine! We look at the urine, because the color and quantity are like a proxy of urine osmolality and ADH activity. 

Jeffrey: I think it is potentially the easiest of tests, which is simply walking to the bedside and looking at their urine.  If their urine yesterday was dark yellow, and today it looks like water, then you’re in trouble, right? So if you go and you see that the urine has become concentrated and then dilute, they’re correcting too quickly. They’re peeing out water, they’re correcting too quickly. Or maybe that’s what you had intended – maybe you were trying to shut off their ADH by giving them volume, and they’re getting of their water because their ADH is shut off. 

S: That is good to know! So looking at the change in urine output and color with more volume or becoming less concentrated can clue us in if we are going in the right direction but also if its going in right direction too fast.

M: If it goes from dark yellow urine to crystal clear within hours “urine” trouble… 

T: But remember, the only problem with relying too heavily on visual inspection of urine is that there are other things besides urine Osm that can affect urine color – this could be meds like rifampin and food like beets. So make your guesses, but still check a UOsm.

M: Okay guys, let’s wrap pearl 3 on urine osmolality.

T: Urine osmolality gives us a snapshot into ADH activity at any given moment. And there are two ways to use it. The first way is to answer is ADH on or off? If the Uosm <250, that dilute urine means ADH is off and the reason for excess free water in the patient is either a high volume intake or low solute state or some combination of both. 

S: But in most cases of hyponatremia, ADH is present and that usually is a urine osm>300; What that tells me clinically is that ADH is around either in response to  some type of hypovolemia or ADH has gone wild, which we will dive into in a sec with pearl 4.

M: The second way to use urine osm is monitor it use it as feedback if what you are doing is moving the patient in the right direction.  Don’t forget that looking at the actual urine can give you a quick idea about the state of the ADH at any given moment.  

T: And don’t forget this, guys – if your patient’s urine is going from a few drops of double hazy bourbon-barreled coffee stout to White Claw just gushing out in front of your very eyes, beware – they may be at risk of overcorrecting. 

M: And your patient has transformed from Millenial to Gen Z in front of your eyes.

Pearl 4 – Urine sodium

UNa tells if you ADH secretion is appropriate or in appropriate by telling you if RAAS is on or not

T: So returning to Ms. Hayveepee our patient in the ED, we already know that they have hypo-osmolar hyponatremia, and we add on that urine osmolality which returns elevated at 600 mOsm/kg.

M: And for those of you snoozing in the back row, remember elevated urine osms means concentrated urine, which means ADH is dialed up.   

S: And now we have to figure out why is ADH on? Is ADH appropriately on or is that inappropriate? But for that, we should first breakdown the appropriate or inappropriate terminology. 

Jeffrey: When we say appropriate or inappropriate, we’re talking about physiology. So in your classic patient with cirrhosis, who has this under-filled physiology where their effective circulating volume is low – that’s appropriate ADH release. It’s inappropriate to you because you’re like “You’re volume overloaded. You shouldn’t have extra ADH.” But it is appropriate because it’s physiologic. Inappropriate ADH release is when you have ADH around, that is not being stimulated by the normal physiologic pathways.

M: So ADH is appropriate in response to either true hypovolemia like severe diarrhea OR in sensed low volume states like in cirrhosis or decompensated heart failure– even if in those patients ADH being on, retaining free water is bad for the patient! 

T: Ok, got it – just because your ADH secretion is not desired in third spacing diseases doesn’t mean it’s inappropriate. Sort of like your weird uncle that you never wanted to turn up for the wedding – they’re still appropriately on the guest list but we’re not thrilled he showed up.

M: Just keep your eye on the envelope Tim.

S: But the question remains – How do we figure that out if the ADH signal we are detecting with high urine osms is appropriate or inappropriate? Which of our hyponatremia lab friends helps us here? 

John: The main purpose of urine sodium is to help answer the question is the ADH that’s being released appropriate or inappropriate. In other words, is it being released by your body in an attempt to maintain intravascular filling or not?

M: Ok waiiiiit a minute. I always thought urine sodium just tells us if renin-angiotensin-aldosterone – or  RAAS is on or not. I never thought that urine sodium is going to help us distinguish between appropriate and inappropriate ADH secretion? 

S: I didn’t either, but we will put together a couple cases in a minute but the pathophys teaching point is that if ADH is appropriately on because of low sensed blood volume, you bet that RAAS will be on too! The idea is the RAAS system is our first body’s first line defense to hypovolemia  and then it activates ADH. 

John: Because when you’re intravascularly depleted, whether for real or in a perceived way, the first thing your body does is it doesn’t increase ADH. It activates the renin-angiotensin system and causes you to retain sodium. Only when that isn’t enough, does it then go on to upregulate ADH and hold on to water, right?

M: Very interesting, so first RAAS then ADH. But how much volume loss does it take for ADH to get going?

Jeffrey: …and we’re not talking like a little bit of hypovolemia, they’re a little dry. It’s gotta be pretty severe hypovolemia. If you remember these curves you saw in medical school, the ADH response doesn’t really even kick in until like 10 to 15% blood volume loss. So we’re not talking like a little bit of volume loss. We’re talking a lot – it should be pretty obvious.

M: Whoa! 10-15% volume loss for ADH release! We will link a nice graph that shows this beautifully in the show notes

Jeffrey: Think about all the patients you see that don’t get hyponatremic when they are volume depleted. There are a lot of them – probably most of them, in fact! They have a UTI or whatever and they’re hypovolemic and they’re hypotensive, but their sodium is fine. It hasn’t been enough for them to get ADH release and as a result hyponatremic.

T: So that really hammers home that if the sensed volume is low enough for ADH to be on, you can bet that RAAS will be on as well. And that’s where urine sodium can help us.

M: Ok so real quick urine sodium basics: the “slam dunk” thresholds here at Urine sodium of < 20 and > 30, with a frustratingly common middle territory that we’ll get to in a bit.  So if the urine sodium is below 20, we are fairly confident that those beans are sensing low effective blood volume.

Jeffrey: If the urine sodium is low, then you can say with some certainty that their sodium-avid, and that means that the body wants to hold on to more sodium. And the reason their sodium avid is because angiotensin-system resulting in more proximal tubular reabsorption, and aldosterone is resulting in more distal tubular reabsorption of sodium. And of course, water follows the sodium and you become more volume replete. 

M: And on the flip side – if UNa is > 30. 

Jeffrey: Assuming that the patient hasn’t been on diuretics and you can measure the urine sodium appropriately, then if it’s not low, then RAAS is probably not on. 

M: And keep in mind we need to interpret the sodium with caution if that urine’s a-pourin. 

John: And this is also on the assumption that they’re not making a ton of urine. If they were making a lot of dilute urine, then the urine sodium is not helpful – it’s just diluted.

S: Ok so to put this together with two scenarios, lets say you get labs back and our patient has a high urine osm but a low urine sodium <20?

T: Ok high urine osm and low urine sodium. They line up well to tell me the body is sensing low effective blood volume! A low urine sodium means RAAS is on and the high urine osms tells me that there is quite a bit of true or sensed hypovolemia that ADH is also on.

M: Ok and the second scenario; What if the labs come back and the patient has high urine Osms and a high UNa…what does this mean?

T: Whoa whoa whoa! High urine Osm and High UNa…this relationship just feels wrong to me, like a peanut butter and mayonnaise sandwich. 

John: So if you send the urine sodium and it’s high, and that suggests that your kidneys have no interest in holding onto sodium, that should make you stop and say for a moment, this scenario no longer makes sense. I am saying that the person is releasing ADH to try to defend intravascular volume, but they’re not holding onto sodium. That’s not an internally consistent. So either I have to come up with another reason for why the urine sodium is high. Like for example, they’re on diuretics.. so they’re wasting sodium, or my theory has to be revised.

T: Our theory likely should be revised because the high urine Osms are telling us that ADH is on, but the high urine sodium is telling us that RAAS is off, which means sensed blood volume is just fine – so what the heck is all that ADH around for? This, ladies and gentlemen, is the definition of inappropriate ADH secretion.

M: Y’all can’t see me but I’m standing and slow clapping. In these cases, we all love it when urine sodium is > 30, without diuretics on board, you can clearly pin it on inappropriate ADH. And on the flip side also nice when urine sodium is undetectable… But what do we do in those situations where it’s between 20s-30s? Because let’s be honest, urine sodium is always between 20-30…. 

Jeffrey: The FeNa (fractional excretion of sodium) is a more sensitive measure of sodium reabsorption or sodium avidity than the urine sodium alone. If you find that a urine sodium is not as low as you would expect it to be – maybe 20 or 30 – and you calculate a FeNa, you should trust the FeNa, because that is a more sensitive measure.

M: The FeNa?! Of all the dramatics! FeNa – this is an AKI guy, right? Am I wrong? What is happening here? 

T: I know right! But remember what FeNa is – its a fancy equation that adjusts that urine sodium to other solutes in the urine and the blood. 

John: We’re all familiar with the use of FeNa in the context of acute kidney injury, right? Less than one suggest the patient’s prerenal, their kidneys are sodium avid. But there’s no reason you can’t use FeNa in the workup of hyponatremia. It’s just that you can’t use the same 1% cutoff as you would with AKI. And that’s because you have to remember people with normal GFRs will have FeNa of one or even less. And that’s because the total amount of sodium that a healthy person filters is so high. So when you have a hyponatremic patient with normal kidney function, their FeNa will have to be much, much lower than one to convince you that they are sodium avid. How low? That’s a subject of some debate, but it’s probably somewhere between 0.5% and 0.15%.

T: So what it boils down to is – when your urine sodium is sorta indeterminate, check a FeNa, and if you get a value less than 0.5% or to be on the safe side, 0.15%- you’re done. RAAS is on.

M: And we also know that urine sodium interpretation isn’t really valid in patients on diuretic therapy, since these drugs work by blocking the kidney’s ability to reabsorb sodium. 

T: And just like in patients with AKI, it’s FeUrea to the rescue!

Jeffrey: We can use it with some degree of diagnostic accuracy assessing the renin-angiotensin-aldosterone system in an indirect way. We want to do it through sodium, but we can’t. So we use a second cousin of sodium – because it follows sodium in a lot of ways in the nephron.

S: So, we use FeUrea because urea is not directly affected by diuretic use. So here, FeUrea <55% is like a urine sodium <20 or a FeNa <0.5%- it points to RAAS activation and some sensed hypovolemia.

T: And more is more here guys. In the early studies where these cutoffs were established, the combination of FeUrea <55% and FeNa <0.5% was better at predicting fluid responsiveness than either parameter alone.

S: Ah love me multiple data points to go by! But in addition to a patient being on a diuretic, the other time there may be low effective blood volume and a HIGH urine sodium (remember, those just don’t agree with each other) and its in rare scenario primary adrenal insufficiency where both cortisol and aldosterone deficiency so all that sodium is being peed into the urine.

M: Got it. Shrey, let’s summarize pearl 4 on urine sodium. 

S: Sure, so what I am taking away is that in a hypotonic hyponatremic patient who has high urine osm and I know ADH is reabsorbing water back into the body, causing that hyponatremia, its the UNa can answer two Qs: is ADH is appropriate or inappropriate? And if the RAAS system active or not? 

T: If RAAS is not active BUT ADH is being secreted (so cases of UNa >40 and UOsm >200), this is the definition of inappropriate ADH secretion.

M: And I’m still slow clapping! The other mind-blower in this pearl was the re-emergence of FeNa, but in hyponatremia. In this setting we’re using it in that all-too-common indeterminate urine sodium between 20-30. Here we are are using lower cutoff of  0.5% – meaning below that we’re in the low effective blood volume world.. And we’ll let John summarize his rule of thumb on fractional excretions in hyponatremia. 

John: We can use the fractional excretion of sodium, of urea, of uric acid. We can use any of these things in anybody. Um, it’s just a question of the threshold that we adopt basically. So I think the one sentence that is always true is the lower, the fractional excretion of blank, you know, be it urea or sodium or uric acid, the more likely it is that, that patient is in fact hypovolemic or is in fact sodium avid. But once you try to pin yourself to a threshold, you know, below which everybody is, you know, sodium avid above which everyone is not that’s when you run into trouble, that that’s the problem. 

Pearl 5 – Uric acid

T: So getting back to our patient in the ED – remember, we already found that she had a low SOsm, an elevated UOsm, and so we add on a urine sodium and the result comes back riiiight in that unhelpful range –  urine sodium 26. Now what??

M: Yes its in the 26 Tim, because its always in the 20s. Here we are going to reach for our last friend, which is serum uric acid…  I like to think of this as the Yoshi of your N64 Mario Kart Game… Like probably not your first choice – that’s clearly Toad or Princess Peach if your racing and Donkey Kong or Bowser if you’re battling… but yeah Yoshi, like serum uric acid, if you’re in a situation where you have to use it you’re not completely upset.

Jeffrey: Like a fourth line test kind of thing. You’re totally like in the dark. And you’re like, I wish I had some other tests

S: So it turns out the serum uric acid can actually give us something to break the tie when you’re between SIADH and something else. 

John: I have consistently found a serum uric acid level to be a valuable thing to send when I am working someone up for hyponatremia. 

M: OK this is definitely a learning point for me. What’s the mechanism here?

Jeffrey: Theoretically SIADH is sort of a volume expanded state, (although it doesn’t have to be), it could be euvolemic. But the physiology seems to be predicated on the fact that the relative increase of volume in the plasma results in some dilution of the uric acid. So they tend to be hypouricemic and hyperuricosuric.

T: So, to translate from nephrology-speak to English – in SIADH, you’ll tend to have low serum uric acid and high urine uric acid – got it. 

Jeffrey: Then the converse is true in volume depletion where you are reabsorbing a lot of it [uric acid]. 

S: The way I make it stick for myself because uric acid gets really complicated, is a watered down version -about it like how the CBC gets concentrated when there’s low effective blood volume states. So similarly, if someone’s volume down I like to think the serum uric acid get concentrated and the serum uric acid is going to be high. 

John: I understand why you wouldn’t want to send a serum uric acid level on someone with CKD, right? Those people are going to have baseline elevations in uric acids level.

T: And the trouble doesn’t stop with CKD – an elevated serum uric acid can be high in a lot of things like gout, kidney stones, hypertension… heck, it can even be higher in men than pre-menopausal women. 

S: But its gonna be the LOW serum uric acid can be helpful in SIADH,  which usually  it’s gonna be less than 4. John also had a very practical reason of why uric acid is his favorite test. 

John: You know, a lot of times people come in with hyponatremia and they’ve already gotten fluid and you’ve got the urine studies and you’re like, what am I going to do? I don’t know how to interpret this. Well, guess what? At our hospital, the lab holds on to the blood for seven days. So if I wanted to, I could add on a uric acid level to the very first basic metabolic panel they had before there was any confounding effect of treatment or time whatsoever. 

M: Woaahhh that’s actually brilliant. So before you guys go flooding your lab with requests for 7 day old uric acid levels, be aware that there are a couple states to be mindful of when using uric acid in this way. 

S: Yep there are a few cases where we see low uric acid in conditions like cirrhosis where there might be reduced hepatic synthesis of it…and naturally endocrinopathies muck this up – specifically thyroid and adrenal disorders. Also rando situations like renal salt-wasting or in cerebral salt wasting where you can also get a low serum uric acid.  

M: But for the most part, low uric acid level can be helpful in pointing towards SIADH and away from low effective arterial blood volume states. And if you want a quick story to drive home how this test might be useful, let’s hear from John again.

John: But it’s very hard to argue with a low uric acid level that is incompatible with hypovolemic hyponatremia. Its like Flat neck veins and trying to tell me that the person has CHF. It does not make sense.That I told you about the one who went to the ICU, I added on the serum uric acid level. It was 2.2 had that resident added on the uric acid level. That would have been enough to be like, this does not make sense to say that this is all hypovolemia that could have avoided this. 

M: That’s is some hard-hitting stuff.

T: Agreed – and since we want to keep in mind those other conditions that can alter serum uric acid levels, one way to improve the diagnostic yield is to calculate a Fe Uric Acid

M: Wait – Fe who? Fe Uric ACID?! 

T: Calm down Marty, its okay- listen just like any other fractional excretion, we’re just adjusting to the plasma level to try and figure out what the kidney is doing with the uric acid it sees. Again, this gets kinda hairy, but generally speaking, we expect FeUric Acid to be higher (like greater than 11%) in states like SIADH. 

S: And the other side of the coin, lower FeUric acid (<11%)would be more consistent in lower EBV states.

M: OK great, Shrey let’s summarize pearl 5. 

S: Yeah so what i learned not give too much mind to high serum uric acid since many things can do it but a low uric acid, generally less than 4 can be helpful to point towards SIADH with cavet is you can also see a low uric acid in cirrhosis or some of the endocrinopathies. If you want more data points for SIADH, in addition to a serum low uric acid, a high FeUric ACID (>11%) can help you feel more confident about SIADH.

And that’s a wrap for todays episode. If you want to learn even more about hyponatremia, check out the corresponding article at Amboss, linked in our show notes. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on instagram or facebook page. Thank you to our peer reviewers Dr. Helbert Rondon and Dr. Larissa Kruger Gomes. Thank you to Shuyi Yang and Solon Kelleher for the audio editing and Dr. Rahul Maheshwai and Preeyal Patel for the accompanying graphic. And thank you to Dr. Sean Burke and Dr. Clem Lee for off-air producing this episode. Stay turned for the next hyponatremia episode on management! As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

References


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