Thread by @HannahRAbrams

Why can TMP/SMX (Bactrim) cause a bump in Cr without affecting GFR?

I learned this fact from a tweet a while back (

https://twitter.com/DrDanRestrepo/status/1199855519072210945

) and it led me to a whole host of interesting learning points about what Cr actually tells us & how drugs are excreted. #tweetorial

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First, what exactly is GFR? Glomerular *filtration* rate is just that: how much is filtered across the capillaries.

Unfortunately for measuring GFR, we can’t place catheters in the Bowman’s space/glomerulus of every nephron & measure— we need markers that don’t change elsewhere.

We measure GFR as the clearance ((U*V)/P) of a markers like inulin or creatinine. In practice, we often look at the change in the denominator (P, or plasma Cr) to track day-to-day changes.

Reach back into your memory of MS1 physiology: what’s the flaw with Cr as a marker of GFR?

Cr is slightly secreted in the PCT by transporters from the OAT, OCT, & MATE families. Inulin is a theoretically better marker (not secreted!), but it isn’t endogenously produced so it has to be injected every time you want to measure GFR. Not something we could do every morning!

OK, so how does TMP/SMX come in? TMP is renally excreted by those same transporters, & competes with Cr. More TMP on board ➡️ more competition ➡️ more Cr stays in the blood. 5/10

pubmed.ncbi.nlm.nih.gov/31176593/

Hold on a second, though. TMP/SMX can actually cause AKI, too. In one study, AKI attributed to TMP was more common than that isolated Cr rise.

What’s the pathophysiologic ddx for AKI d/t TMP/SMX?

pubmed.ncbi.nlm.nih.gov/22351681
pubmed.ncbi.nlm.nih.gov/21856494
pubmed.ncbi.nlm.nih.gov/678832

TMP/SMX can also cause significant drug/drug interactions hepatically & renally. Remember MATE (“multidrug and toxin extrusion protein”)? Several meds incl metformin, dolutegravir, & famotidine are excreted by the same transporter.

pubmed.ncbi.nlm.nih.gov/31176593
pubmed.ncbi.nlm.nih.gov/23305245

Not to leave out the distal nephron, TMP can also cause hyperkalemia via its amiloride-like effect on the ENaC channels of the collecting duct. This can occur with standard dosing but there is ⬆ risk with dose & age.

pubmed.ncbi.nlm.nih.gov/8328738
pubmed.ncbi.nlm.nih.gov/21989472

So, what’ll go through my mind next time I see a patient with ⬆ Cr after TMP/SMX?

Here are some take homes, & for further reading check out: pubmed.ncbi.nlm.nih.gov/21989472/ @DavidJuurlink
pubmed.ncbi.nlm.nih.gov/22351681/

Thanks to @tony_breu & @AvrahamCooperMD for guidance. Check out curiousclinicians.com & the Curious Clinicians podcast for a more detailed discussion of this next month!

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