OUWB: So you’re lost in renal and looking for a map

If you are a reader and need a book to help you understand renal physiology, may I suggest:

Renal Physiology by the Bruces (Koeppen and Stanton) Amazon

It is well written and is targeted at pre-clinical medical students. We are using it for our fellow renal physiology class and I don’t love it for that (no references for one).

OUWB: Podcasts of interest

If you are taking the M2 renal class and are looking for a way to study while cleaning, exercising, walking the dog, or commuting, allow me to suggest a few podcasts that may be of interest.

Curbsiders Podcast on rapid interpretation of ABGs

Curbsiders #104: Renal Tubular Acidosis

The Curbsiders: Hyponatremia

Curbsiders: Hypernatremia

Hyperkalemia with The Curbsiders

Channel your Enthusiasm This is an award winning podcast podcast series on renal physiology. The intended audience is nephrology fellows and clinicians so it may aim too high, but if you like podcasts and a group of experts getting together to geek out on a topic they love it may tickle your fancy.

A long list of interesting podcasts for interested medical student

OUWB 2023: Regarding the upcoming TBL

I received an email questioning what to read in order to prepare for the the iRAT. Should students just review the PDF, or should they also review the lectures?

All of the answers can be found in the PDF, however both the lectures and the PDF cover the same material so reviewing the lectures will not hurt and may be helpful.

Here is a link to the PDF in question

The simplest things are way more complex than we understand

Recent poll I posted to Twitter

This was inspired by a recent patient encounter. Patient was doing great. No complaints. Here for routine follow up. I ordered renal function panel, as I do with essentially everyone I see, every visit.

Their creatinine was up and as I scanned their vitals, the blood pressure was lower than normal. Not really low, but just as their creatinine was higher than normal, their blood pressure was marginally lower than normal.

So now what to do. I felt that since I check the labs and found a loss of kidney function I was obligated to react. Otherwise what am I doing checking the labs, if I’m not going to act on the results.

I put the blood pressure together with the drop in kidney function together and trimmed the patient’s blood pressure medications. I have no idea if I did the patient a favor.

If they come back next visit and the creatinine is down, was that due to the intervention or just reversion to the mean? If it was due to the intervention, was the rise in blood pressure worth the improvement in renal function? Even if there is no change in blood pressure, did the loss of the RAASi and/or beta-blockade expose the patient to other long term deleterious effects?

None of this would have happened had I not happened to check the patient’s creatinine on a routine visit. Is there evidence for us checking kidney function? Is there evidence for routine CKD visits?

Every time I see a bump in creatinine I worry that I am at the beginning of the yellow arrow, but probably we are just riding the wavey red line.

I don’t come to laud the urinary anion gap, I come to bury it

While preparing for the electrolyte session for Epic Pathshala I added a new twist. For the first time I added the concept that Jaime Uribarri has been shouting for the last few years regarding the use of urinary anion gap. I first saw Dr. Uribarri at NKF Clinical at Boston in 2022. He gave a great lunch-time presentation on the utility (more specifically, the lack of urility) of urine anion gap. Perfect counter programming to Richard Sterns’ lecture on managing electrolyte disorders with the assistance of the BUMP (basic urine metabolic panel) (NDT).

Dr. Uribarri’s thoughts were crystalized in two recent articles:

  1. The Urine Anion Gap: Common Misconceptions
  2. Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium

The tweetorial can be found here:

Part One

Part Two

Here is my rough script that I use to write the tweets

This is going to be a long arc and it has a point but it is going to take a bit to get there.  #Tweetorial #MedThread #Electrolytes #AcidBase 1/11

Let’s start with acid base balance. Metabolizing proteins, specifically the sulfur containing amino acids, methionine and cysteine, generates hydrogen sulfide (H2S). This acid cannot be cleared by the lungs. #OnlyTheKidneys can clear this acid. 2/11

This acid load, generated by normal metabolism that must be excreted by the kidneys is the daily acid load. When patients with advanced CKD develop progressive metabolic acidosis it is because they are failing to clear the daily acid load. 3/11

On a “western diet” (I.e. carnivorous diet) it is about 50-100 mEq of acid (H+ ions) a day. 4/11

Boy it would be easy if we could excrete this as free hydrogen ions, alas that would require a urine pH of around 1 (50 mEq H+ in 2 liters of urine). At a minimal urine pH of 4.5, we would need to make 1200 liters of urine a day to clear the daily acid load. 5/11

So the kidney has to smuggle the hydrogen out as something other than free hydrogen. There are two solutions to this:

  1. Titratable Acid
  2. Ammonium 6/11

Titratable acid is just H2PO4–. Most of the daily acid load is excreted this way. The problem is that it is fixed by phosphate intake. We cannot manufacture new phosphate open the spot when we encounter a large acid load, so we cannot ramp up phosphate excretion to deal with an acid load.** 7/11

**Actually that is not entirely true. In addition to the serum bicarbonate, the bones are called upon to buffer an acid load. And as they are dissolved buffering acid (not an ideal state) they release phosphate which clears the acid from the body. 8/11

So when faced with a large acid load we call on system two: ammonium. The physiologists have two models for how this works. In one the production of NH4 from glycine produces two bicarbonate, the other urinary NH3 accepts a hydrogen ion to form NH4. 9/11

We’ll let the physiologists argue over these two models, for our purpose the only thing you need to know is that a healthy renal response to acidosis is an increase in urinary ammonium to excrete the excess daily acid load. 10/11

The problem comes from the fact that when you order a urine ammonium the labs tells you to pound sand. They won’t do it.They can use the same instrument they use to measure serum ammonia (though they would need to dilute the urine sample 40:1). Because the lab wouldn’t measure urine anion gap lead to 40 year distraction called the urinary anion gap… 11/11

Okay, on to part two. 

Let’s review, the kidneys excrete 50-100 mEq of H+ ions every day as what we call, “The daily acid load”

Most of the daily acid load is excreted as H2PO4–, AKA Titratable acid

An insignificant < 1% is excreted as free hydrogen and that can be detected as urine pH.

And most importantly, for our purposes, in the face of an acid load, that excess acid is excreted as NH4+ 1/

Clinical labs generally refuse to measure urinary ammonium so doctors have been forced to scramble to find ways to “estimate” urinary ammonium. 2/

In 1986 electrolyte legend, Mitch Halperin published this paper which discovered an amazingly tight correlation between urinary anion gap and urinary ammonium.  3/

This makes sense. The typically measured urine electrolytes are sodium, potassium, and chloride. If there are a lot of positively charged ammoniums in the urine, the urine chloride better increase to balance those cations out. Can’t have people peeing sparks. 4/

Discoveries are made in JCI, but standard of care changes with NEJM. And sure enough, 2 years later, NEJM published this “proof” of the urinary anion gap. What an amazing time that the NEJM would publish 60 person physiology studies 😍 5/

So for forty years this schema ruled the nephrology wards.

Patients with non-anion gap metabolic acidosis would have urine electrolytes checked in order to see if their kidneys were responding appropriately. 

A negative urine anion gap indicated a rich supply of urinary ammonium indicating a healthy renal response and would direct physicians to look to the gut for the cause of metabolic acidosis.

A positive urinary anion gap indicated a kidney that was unable to excrete excess ammonium and suggests a diagnosis of distal or hyperkalemic (type 1 or 4) RTA. 

But a few years ago Dr. Uribe began making noises that this whole urinary anion gap went against fundamental laws of nature. Na,Ley that urinary na, k, and cl are not there to merely balance charges but that their urinary excretion is dependent on dietary intake.

Uribe pointed out that patients would have volume depletion(due to extra-renal sodium losses) and as a result would lower urine Na, resulting in the negative gap. Similarly in the healthy controls ion Batille’s study, they had been loaded with oral NH3Cl. The excess chloride he argues would make the urinary anion gap negative. 

He then points to studies of DKA, respiratory acidosis, and systemic acidification that all result in increases in urine ammonium but do not make the urine anion gap more negative.

And here is the Keynote presentation I used to generate the images

Keynote

PowerPoint

Edelman formula is fundamental to understanding sodium

Sodium is wildly misunderstood and mismanaged.

If you want to understand sodium you should spend the time to truly understand The Edelman Formula. I have seen no better explanation of this formula than this powerpoint by Graham Gipson (who incidentally also designed the 2023 NephMadness logo). It is 133 slides long, but he has printed each build of the slides separately, and I found it fairly self guided. He beautifully shows how the EdelsonFformula can be derived using first principles and algebra and ends with demonstrating how the formula (nearly) perfectly predicts the results of Edelman’s classic 1958 experiment.

Sometimes I need a post just as a landing page for a talk.

Here are a bunch of references for urinary anion gap. Time to move on guys, this equation doesn’t work .

The first publication about urine anion gap. Link

Goldstein, M. B., Bear, R., Richardson, R. M., Marsden, P. A., & Halperin, M. L. (1986). The urine anion gap: a clinically useful index of ammonium excretion. The American Journal of the Medical Sciences, 292(4), 198–202.

The second publication, and in the NEJM no less. You don’t see these kind of physiology experiments make it to NEJM any more. And that is kind of a shame. Link

Batlle, D. C., Hizon, M., Cohen, E., Gutterman, C., & Gupta, R. (1988). The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. The New England Journal of Medicine, 318(10), 594–599.

Urinary anion gap take down. Might not be first, but the first I heard this argument was by Dr. Jaime Uribarri at NKF Clinicals. Link

Uribarri, J., & Oh, M. S. (2021). The Urine Anion Gap: Common Misconceptions. Journal of the American Society of Nephrology: JASN, 32(5), 1025–1028.

Another editorial showing the way forward: Just measure the urinary ammonium. Link

Uribarri, J., Goldfarb, D. S., Raphael, K. L., Rein, J. L., & Asplin, J. R. (2022). Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation, 80(5), 667–676.

Urine anion gap does not predict urinary ammonium in DKA Link

Oh, M. S., Banerji, M. A., & Carroll, H. J. (1981). The mechanism of hyperchloremic acidosis during the recovery phase of diabetic ketoacidosis. Diabetes, 30(4), 310–313.

Urine anion gap does not predict urinary ammonium in respiratory acidosis Link

Polak, A., Haynie, G. D., Hays, R. M., & Schwartz, W. B. (1961). Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. I. Adaptation. The Journal of Clinical Investigation, 40(7), 1223–1237.

Urine anion gap does not predict urinary ammonium after systemic acidification with oral methionine loading Link

Lemann, J., Jr, & Relman, A. S. (1959). The relation of sulfur metabolism to acid-base balance and electrolyte excretion: the effects of DL-methionine in normal man. The Journal of Clinical Investigation, 38(12), 2215–2223.

I helped create a significant manuscript on hyponatremia

I have been an avid reader of the hyponatremia literature for my entire medical career and last week I contributed to a significant new manuscript to the dysnatremia canon.

This link is supposed to work to give people access to the full text of the manuscript.

This feels like a major career achievement. For once I’m not just talking and teaching about other people’s work but sharing my own work, and in a topic I care a lot about. I am so grateful to Michael Fralick who approached me about helping out on the study way back in 2019.

ADH stood for Association with Demyelination in Hyponatremia

Amazing to see it mature from idea to data to manuscript.

The article looks at the rate of osmotic demyelination syndrome in hyponatremia and it is the largest examination of this question that I am aware of. I posted a Tweetorial on the topic here:

And what follows is the draft of the tweetorial (minus the gifs)

Never in the history of medicine has so much been done, by so many, so incompetently, with so little consequence as in the treatment of severe hyponatremia. #Tweetorial  1/10

We all know that we cannot correct hyponatremia too fast and that the speed limit is 8 mmol/L per day. We know this. We still do a terrible job at it. In the landmark George study, 41% of 1,490 patients had their sodium corrected faster than 8 mEq/L. Look at the poor slobs at the left of the graph whose Na actually went down in the first 24 hours 🤪 2/10

Thankfully this incompetence is rarely punished. Of the 611 (41% of 1490) patients who over-corrected in the George trial, only 7 developed osmotic demyelination syndrome (ODS). Screw the sodium correction and you can get away with it 99% of the time. 3/10

I had the good fortune to be invited to help with a research study looking at the incidence of ODS in hyponatremia using the GEMINI database which tracks internal medicine admissions in Toronto. It is amazing that someone you look up to and respect from the medical literature DMs you to join them on an important study. Thanks @FralickMike 4/10

So the gemini database was used to look up every case of hyponatremia (Na < 130) admitted to one of 5 academic hospitals in Toronto from 2010 through 2020. 

22,858 cases of hyponatremia. This is a massive study. By far the biggest ever. If you restrict the cohort to just people with a sodium < 120, it is nearly twice the size of George. 5/10

And the Canadians did a better job of correcting the sodium, but still went too fast in 18% of cases, 3632 patients. But hold on, a lot of these people had relatively mild hyponatremia (relative to George). When you break it down by starting Na, Canadians look just as bad the US at fixing the sodium slowly. 6/10

And what was the consequence of all that hyponatremia? And all that rapid correction? Twelve cases of osmotic demyelinating syndrome.
12 out of 22,858 cases of hyponatremia. 0.05%

If you divide by starting Na they found an incidence of:  

0.3% with a Na < 120

0.015% with a Na > 120

2.5% with a Na < 110 7/10

The part of the manuscript you are looking for that is not there is rates of ODS by rapid versus slow correction. We could not publish this because of the ethical guardrails on this trial. And the statisticians wouldn’t even whisper it in my ear because they know me. Kind of a bummer.  8/10

So what can we take from this paper? ODS is rare, Canadians are just at bad correcting the sodium slowly as the guys in Pittsburgh and the rate of ODS errally goes up as the initial sodium level goes does down, from a trial 0.015% at levels > 120 to 2.5% with sodiums < 110. 9/10

Take a look at the paper and at the George paper.

https://evidence.nejm.org/doi/10.1056/EVIDoa2200215

https://pubmed.ncbi.nlm.nih.gov/29871886/

10/10

Addendum:

Brian Locke asked how I made the gifs in the tweetorial

Did you make the animations? If so, they are awesome and I’d be interested to know how. #MedEd

Also, great study 👏

Originally tweeted by Brian Locke (@doc_BLocke) on March 30, 2023.

They are simple animations in Keynote. Here is the file so you can see how they work.

If this is interesting to you, don’t miss the editorial by Ayus. He’s ready to burn everything to the ground and he called his own number a few times in the refs.

The future of nephrology

Super fun discussion on Twitter that has spilled out over the last few days. It began with this tweet about Nayan’s take on the latest MRI imaging during dialysis.

The original article is here and I’m a bit embarrassed about my sensationalization being a bit overwrought.

Forunaltely, it did trigger a great rolling conversation about the future of dialysis and by extension, nephrology. It may be difficult to recreate the discussion from that original tweet, so here are some key tweets:

In the midst of this discussion I broke the thread and added novel tweet asking people to place a bet on the future of transplant.

But this prognostication is focused on emerging transplant technologies and fails to capture the full breadth of nephrology transformation that we are seeing. With the emergence of Flozins, GLP1 agonists, MRAs (both steroidal and non-steroidal) as well as the increased interest and development of novel treatment targets, it is not a leap to say that nephrology in 10 years will look very different than it is today.

How will we mark that development? My poll of when will more than half of transplants come from non-human sources is a specific and quantifiable time that will represent a sea change in transplant. A marker that represents a change not in potential but in delivery. So how will we mark that moment in nephrology at large? I would argue that it happens when we see consistent year over year fall in the number of prevalent dialysis patients (in-center and home) for four consecutive years.

So how long until the combination of slower CKD progression, increased transplantation, and, unfortunately part of the equation, continued stagnation in dialysis longevity, result in consistently falling dialysis prevalence?

Sodium is not like the other electrolytes

This thread by Screaming Pectoriloquy is perfect

And a screenshot for when Twitter disappears.

A ten percent reduction in sodium drops it from stone cold normal to rather significant hyponatremia. This is a great example of how precisely sodium is regulated. Sodium regulation is tighter than all other ions. Look at a CMP with calcium, phosphorus, and magnesium added in. (Data is from UCSF).

Range is calculated by taking the difference between high and low and dividing it by the low value. https://www.ucsfhealth.org/medical-tests/phosphorus-blood-test
https://www.ucsfhealth.org/medical-tests/magnesium-blood-test
https://www.ucsfhealth.org/medical-tests/comprehensive-metabolic-panel

Here is a graph of the spread.

Two things immediately should be obvious.

    1. BUN (233%) and creatinine (117%) are not regulated anywhere close to how electrolytes are regulated. Get those guys out of here.
    2. And, the sodium (7%) and chloride (10%) range are nearly identical. Outside of the anion gap, I almost always ignore chloride. 

So let’s simplify this and remove the outliers and shadow.

Look at how tightly sodium is regulated. Regulation of second place, calcium, is THREE times as relaxed.

Every electrolyte is important, but regulating sodium regulates the tonicity in all 42 liters of the internal ocean. Apparently, this is important and sodium is allowed to wander only slightly.