Precious Bodily Fluids

Dear Dr. Topf,

I hope you are doing well! My name is XXXXXX and I am a second year medical student at OUWB. Thank you for your excellent lectures [ed: I added the bold because I love flattery] that you gave yesterday on sodium and water metabolism. During the second lecture, I did get a little confused on some of the core concepts regarding hyponatremia. I am trying to conceptually understand why your urine volume decreases when you have low solute and high amounts of water intake. 

I can see why you are confused, let me try to reteach this.

This slide is supposed to demonstrate how the kidney handles water and solute.

In the absence of kidney failure, solute absorption = solute kidney excretion. Often this will be abbreviated solute in = solute out since our indescrimnate GI tracts pretty much absorb all the minerals and protein they are exposed to and, besides the kidney, no other organ system does meaningful solute excretion. In fact, a failure of solute in = solute out to hold true is a pretty good functional definition of kidney failure.

For people on a western diet (i.e. omnivorous) solute intake can be estimated at 10 mOsm per Kg body weight. So for the 70 kg adult, estimate solute load at 700 mOsm per day.

The kidney can get rid of that solute load in a variable amount of urine. If the person is drinking a lot of water, lowering body osmolality, the hypothalamus will detect this and decrease ADH resulting in dilute urine as indicated on the left side of the slide (absence of ADH, urine osm of 50) and get rid of that solute load with 14 liters of water. The loss of 14 lite3rs of water will increase the serum osmolality back toward normal.

If the patient has a low water intake (which will push the serum osm up) or high serum osmolality, the hypothalamus will release ADH and the urine osm will increase so the body will excrete that same osmolar load of 700 mOsm in only 0.6 liters, retaining any water intake in excess of this 0.6 liters. This retained water will dilute the serum osmolality back toward normal.

This is supposed to demonstrate that the kidney can get rid of the daily osmolar load in a wide range of urine volume to balance water intake and excretion in order to maintain homeostasis. 

The next slide shows what happens when the patient is not on a normal western diet. In this case instead of eating 700 mOsm a day the patient is only taking in 100 mOsm a day

Now with ADH turned down to zero, and the urine osmolality bottoming out at 50 mOsm/Kg H2O the maximum amount of urine the body can produce is only 2 liters, an amount that people may exceed with normal, habitual fluid intake. The serum osmolality is low and the body wants to get rid of excess water, but turning down urine osmolality does not produce the expected copious amount of dilute urine needed to correct this situation, because the urine volume is limited by a lack of ingested solute. To increase the urine output to 3 liters would require 150 mOsm of solute (3 L x 50 mOsm/g H2O) but they are only eating 100 mOsm! So while in most cases urine volume is determined by ADH, with increasing urine volume with decreasing urine Osm, once the daily osmolar load is excreted no more urine can be produced. 

If the patient has hyponatremia, wouldn’t the interstitial medullary gradient not form due to little sodium being filtered in the tubules at all and thus leading to low amounts of sodium leaving the NKCC2 proteins, thus leading to lower amounts of water being reabsorbed (this is how I’m currently thinking and why I am getting so confused)? 

This is not proper thinking. An example of severe case of hyponatremia would be a sodium of 110 mEq/L. Given a GFR of 100 ml/min (0.1 L/min), this is still:

110 x 0.1 L/min x 1440 min/day = 15,840 mEq of Na filtered. 

Plenty of Na to keep the medullary interstitium fully concentrated. Also remember half of the osmoles in the medullary interstitium are urea which is not really affected by the hyponatremia (not entirely true, but true enough for MS2s)

I am also aware that ADH is still going to be low here because you wouldn’t want to continue reabsorbing water with hyponatremia, 

True

so this is also why I got confused and thought you’d be producing a higher volume of urine rather than a lower one. With the patient drinking lots of water AND having low sodium (hyponatremia), can you reiterate what happens? 

When the osmolality is low the body will suppress ADH, unless there is some other stimuli of ADH: volume depletion (hypovolemic hyponatremia) decreased perfusion (hypervolemic hyponatremia from cirrhosis or heart failure) or SIADH. THe lack of ADH  increases urine production until all of the daily solute is excreted. With a normal diet, the 700 mOsm will allow the production of 14 liters of dilute urine, enough to correct just about any hyponatremia. But if the patient is drinking 15 liters of water, even with maximally dilute urine there will be progressive hyponatremia, must have fluid intake below excretion to normalize serum Na.

Hope this helps

Link to PDF of the above GiF

Link to Keynote of the above GIF

Link to PowerPoint of the above GIF

We had a patient with an active infection and bilateral below the knee amputations. The Creatinine was obviously going to over estimate kidney function due to the low muscle mass and I wasn’t prepared to trust the cystatin C in the presence of active inflammation. What to do? Can we McGyver the GFR by looking at the fall in vanco levels over time? Yes, of course we can.

Here’s how it works. Vancomycin is primarily eliminated by glomerular filtration, so its clearance approximates the GFR.

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1. Get two vanco levels

You need two vancomycin concentrations drawn after the distribution phase (ideally 1–2 hours post-dose and a trough) and without an additional dose in between.

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2. Calculate the Elimination Rate Constant (ke)

This gives you the rate at which the drug is disappearing from the plasma.

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3. Estimate vancomycin Clearance

Vancomycin’s volume of distribution (Vd) is about 0.7 L/kg.

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4. Convert to GFR (mL/min)

Since vancomycin is almost entirely renally cleared, its clearance approximates GFR.

The vanco clearance calculated above is in liters per hour, so to get conventional GFR units, multiply by 1000 and divide by 60

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5. Caveats

• This only works if renal function is stable (no AKI or wild fluid shifts)
• Must use post-distribution levels
• Non-renal clearance of vancomycin is minimal but not zero
• Vd can be wildly off in critical illness, obesity, or fluid overload

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Bottom Line

You can use vancomycin estimate GFR. It’s not perfect, but in the right context it’s a clever way to triangulate kidney function when the usual suspects lie.

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I find using LLMs is a bit like skipping stones on a lake – in the right domain with the correctly-worded prompt, you can sometimes get impressive output.And sometimes you get an utterly unceremonious "kerplunk".

— Ryan Radecki MD MS (@emlitofnote.bsky.social) 2025-02-23T20:04:37.221Z

I had a patient’s potassium pop from 3.1 to 5.1. It struck a half-remembered dream of a mentor teaching me that the most common cause of hyperkalemia was the treatment of hypokalemia. It is one of those internship myths that are recited mostly just to scare caution into over eager interns. So I asked Bluesky if anyone knew about this.

I once was told that the most common cause of hyperkalemia was mistreatment of hypokalemia. Anyone know of a reference to support that?

— Joel Topf (@kidneyboy.bsky.social) 2025-02-23T14:49:39.182Z

I then immediately, I went to Chat GPT4o and asked the same question. I hit the right domain with a correctly-worded prompt and the rock skipped clear across the lake.

Looking at my choices, I went with the middle one, because it had a DOI and I don’t have a subscription to UpToDate.

And being from 1998 made it contemporary with the pearl of wisdom in question.

The NEJM review of Hypokalemia by G. John Gennari was part of a review series on Fluids and Electrolytes the NEJM ran around the turn of the century. They were foundational articles for me as a fellow from 2001-2003. And on page 6 of an 8 page review of hypokalemia he drops this bomb.

Reference 53 is a study that G. John Gennari published in 1987.

In that study he combed the lab computer to find every case of hyperkalemia over 5.9 in a year. He found 300 and examined every case. Forty-eight of them were associated with new medications. Here was his list of meds that could cause hyperkalemia

Notice he doesn’t include ACEi as a group. He uses group names for beta-blockers and potassium sparing diuretics. But he lists captopril as a single agent because there were no other ACEi. This is an old study.

Of those 300, 172 had sustained hyperkalemia. He found 43 to have a single etiology of hyperkalemia (Group 1). And of those 43, potassium chloride was the sole etiology in 29 patients. Renal insufficiency was right behind at 24, followed by digoxin at 21. Did I mention this was an old study?

The whole study sounds pretty flimsy and polluted with biases. It stinks of post hoc choices and arbitrary rationalizations. Research has become much more rigorous in the last 40 years.

I don’t find this data to be cempelling but I’m also sure this was the source of the myth in question. And Chat GPT4o was instrumental in finding it and finding it fast.

That said the discussion on Bluesky was absolutely delightful. Follow the original post to see the rich conversation that bubbled up.

Post script: I do not believe that the most common cause of hyperkalemia is the treatment of hypokalemia. I think we live in a world with so much angiotensin and aldosterone inhibition that mistreatment of hypokalemia is a tiny blip on the radar.

That seems uncommon these days (suspect MRAs, RASi, etc). If anything, most hypoK cases are tail-chasing quests that never fully correct. In that ‘87 paper, pt must have an underlying renal issue 2 switch 2 hyperK, did they? Like we discussed in the podcast, it’s never just the bananas!

— Juan Carlos Q Vélez, MD (@juancarlosqvelez.bsky.social) 2025-02-23T19:10:41.515Z

Post-Post Script: the first reference, the review from 2017 in the NEJM by Kamel and Haperin, It doesn’t exist. The computer is pulling their book from 2016.

This came up on rounds today. I thought I covered this on the blog before but if I did, Google failed me. The answer is 7.7 mEq of Na and 7.7 mEq of HCO3 in every 650 mg tablet of baking soda.

This is just 650 mg divided by the molecular weight of NaHCO3, 84 mg/mmol.

I spend a lot of time talking about how incredible the kidney is but then sometimes you see kidneys that just don’t do anything. I was in the hospital and we had a patient develop acute on chronic kidney disease. Following a few days of anuria they started to make urine so we checked urine creatinine to see how well the kidney was recovering.

Not good, Bob.

The patient had among the lowest urine creatinines I had ever seen. Compare the urine creatinine of 14 to the serum creatinine of 10 and you see the laziest nephron ever. It is barely altering the composition of the urine at all.

The patient also had the highly unusual situation with urine Na greater than serum Na. I think I have only ever seen that in cases of severe hyponatremia due to SIADH.

This patient had a fractional excretion of Na of 70%. Amazing. Normally the kidney reabsorbs 99% of the filtered sodium, here 70% of the filtered sodium just flies by.

This helped our discussions on the patient’s renal prognosis. The urine they were making was a useless gasp of a dying organ.

The first newsletter of 2025 and 30th newsletter for MashUp MD, successfully focuses on various topics while avoiding discussion of the new Trump administration.

Read it here (and subscribe please)

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So I just pushed out the latest episode of Channel Your Enthusiasm. This one was recorded in November of 2022. (Yes, I am a little behind on the editing, but I have a new workflow and its name is Simon Topf. Things are going better.) During the recording Josh mentioned that we had just won the ASN Innovations in Education Award and Melanie pipes in we won the 2022 version of the contest because even then we knew that it was going to be awhile before the episode was published and we all assumed that there would be other, subsequent winners.

Nope

2022 was the last year of the ASN Innovations in Education Award.

The website says that they are skipping 2023 and to check back in 2024

I asked about the contest on ASN Communities and got the following reply:

Hello, Dr. Topf,

Thank you for your post. ASN decided to pause the Innovations in Kidney Content the last couple of years due to declining interest. ASN continues to offer the William and Sandra Bennett Clinical Scholars Program: https://www.asn-online.org/grants/tig/details.aspx?app=BENNETT and the Harold Amos Medical Faculty Development Program Award: https://www.kidneycure.org/grants/faculty-development.aspx 

Sincerely,

Charyl Delaney

The Channelers had a discussion about the award, which you can hear here

The audio is from the podcast recording, most of which ended up being cut from the episode. The images are from our video application for the award. You can see that video with the original audio, here. In the video we discuss how the winners were announced. Edgar took a video which i now on You tube. Take a look:

Awards given by professional societies is one of the ways that an organization can demonstrates its values. And the ASN Innovations in Education Award told the world that nephrology valued education and educators. Unfortunately, we live in a world where promotion and tenure committees undervalue the work that goes into educational initiatives. During my most recent tangle with P&T they expressly said that when outlining what you do for the medical school, to not include teaching, as that is just table stakes and not that important. The ASN education award provided a bit of incentive to pursue big audacious educational projects.

Some of the discussion was about how slipshod the award recognition was in 2022. This was a change from previous years and we couldn’t figure out why. Now it is apparent that the organization had already walked away from Innovation Award.

This is a disappointment. I am sorry to see it go away.

The latest salvo in the hyponatremia wars takes off where Seethapathy left us (NEJM Evidence | NephJC). Last week, Juan Carlos Ayus published his latest study (JAMA Internal Medicine) on hyponatremia, a meta analysis of patient outcomes in the management of hyponatremia.

If you are not aware of Ayus’ prior hits, you should take a look.

Retrospective data that looks at speed of correction and uses that to look at outcomes has been a staple in hyponatremia research for decades. It is the basis for the current, decades-old, hyponatremia guidelines from the US and Europe. However, until recently the only outcome of interest was osmotic demyelinating syndrome (ODS, and boy is that a loaded term that probably should be re-litigated, see Seethapathy’s grand rounds in Ottawa, YouTube). When looking at ODS, a pattern emerges that slower correction is associated with fewer cases of hyponatremia, however it is unusual to look at a case series and only care about one outcome. If we pull back a bit and look at all the outcomes that matter, things like length of stay and mortality, the situation changes. In Ayus’ meta-analysis, the primary outcome was mortality and just like in Seethapathy, slower correction was associated with increased mortality. Not a great look. And I think the orders of magnitude are important here.

Patients that experience faster correction of sodium consistently have better clinical outcomes in these sorts of analysis. And the rate of ODS is vanishingly low, expecially with the looming specter of death. The focus on ODS makes us ignore what an ominous sign hyponatremia really is. I can’t think of an electrolyte with such a frightening association with mortality.

The obvious weakness with this type of analysis is they do not provide any insight as to why the correction was slow. While we like to think that the slow correctors are populated by patients with bespeckled nephrologists carefully calculating sodium and water prescriptions according to the Edelman formula, but the reality is that the patients with slow correction is populated by people with liver and heart disease that are not easy to fix. And their prolonged length of stay and poor outcomes are driven by these dismal diagnosis.

And what of the rapid correctors? This cohort gets better quickly, not because cowboy nephrologists are slinging 3% saline to rapidly bring the sodium to heal, no, rather these are patients whose body wants a normal sodium and as soon as it is able to reject the excess water it will return the sodium to normal. And this is often despite the best intention of the treatment team. In Sterns’ study on the DDAVP clamp, 25% of patients in the control group (historic controls for their retrospective case series) made more than 1200 ml of urine an hour.

The slow correctors is populated by patients who are so ill that their bodies have rejected sodium and water homeostasis in the name of perfusion. Not a good place to be, hence the bad outcomes. While the fast correctors is populated by people whose physiology remains committed to sodium and water homeostasis. It is not hard to see why disease so severe that it rewrites the laws of homeostasis would have increased rates of devastating outcomes.

More simply the results are confounded.

Does the confounding explain all of the excess mortality?

Is it that far fetched to believe that the low sodium itself could contribute at least a little to the excess mortality seen with hyponatremia? It seems likely that something the body spends so much energy trying to keep regulated would be important and have an effect on outcomes. And given the rarity of CPM/ODS, even a small residual effect would swamp the concern for CPM/ODS because not only is ODS, rarer than we were lead to believe, the outcomes of ODS are not as bad as we were taught.

In Jason George’s study of nearly 1,500 people with sodiums less than 120, they had 9 patients with ODS on imaging. In terms of neurologic outcomes among these 9, “five patients with documented osmotic demyelination had recovery with no neurologic deficits, two patients died from unrelated causes, and two were lost to follow-up.”

When you look at Ayus’ meta-analysis of hyponatremia are you sure there is no residual signal? Because the people promoting ever slower rates of correction to avoid CPM feel that there is nothing on the other side of the balance pan. That slowing the rates of correction will always be justified. That it is okay to prolong hospitalization by any length of time. That we should adopt interventions like DDAVP clamps without any prospective data because the risk of ODS is so important that concern for this complication should drive the therapeutics in hyponatremia.

And while we are adopting DDAVP, we should restrict and avoid tolvaptan, not because it causes ODS, there were no cases in Schrier’s Phase three SALT1 and SALT2 trials, but because it may correct the sodium faster than guidelines suggest. Now we are not even worried about ODS, but rather the purported risk factor for ODS, speed of correction.

We adopted the risk factor rather than the outcome in the case of hypertension. We want to avoid the stroke and CV death, so we treat the blood pressure to a target BP. But the hypertension guys didn’t just look at retrospective data. They went out and did the work to see if treating blood pressure avoided the outcome, and it did. We should demand similar certainty for the treatment of hyponatremia.

We no longer should accept retrospective observational data. The Hyponatremia Intervention Trial (HIT, Protocol and rational for design publication in PubMed) showed that we could do prospective, randomized trials, in the treatment of hyponatremia. The study was not positive, but it was important. Here are my tweets from the Late Breaking and High Impact Clinical Trial Session at Kidney Week where the results were announced. We are still awaiting publication.

Made it to the LBCT sessionAnd it is a hyponatremia trial!#KidneyWk

— Joel Topf (@kidneyboy.bsky.social) 2024-10-26T17:47:32Z

It is time to demand this. Hyponatremia is too common for us to trust that the mortality signal is entirely a statistical mirage.