Author: Joel Topf

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