Nephrogenic diabetes insipidus and carbonic anhydrase inhibitors

Nephrogenic diabetes insipidus (NDI) is incredibly difficult and frustrating to treat. If the cause of NDI is loop diuretics, hypokalemia or hypercalcemia, it is a trivial problem, however in patients with congenital NDI or lithium induced NDI the treatment options are limited and pretty ineffective. The standard game plan is administering thiazide-type diuretics paired with a low salt/low solute diet. Here is the page from The Companion:

I think the first question is one of my favorites in the entire book.

Recently there has been some noise that carbonic anhydrase inhibitors maybe the way to go in lithium induced NDI.

Lithum causes NDI in two stages. In the first stage, lithum induces a down-regulation of the aquaporin-2 channels. The second stage comes from loss of the aquaporin-2 expressing principal cells of the collecting duct. To compensate there is an increase of alpha-intercalated cells.

The theory that HCTZ improves NDI through volume deficiency first took a hit in 2014 when Anne Sinke, and company showed that mice with lithium induced NDI but without the thiazide sensitive sodium-chloride co-transporter (NCCT) could still reduce urine volume in response to thiazide diuretics.

Let that sink in for a moment...mice that do not have the thiazide sensitive NCCT respond to thiazides as expected in regards to lithium induced NDI. This finding required an explanation and the authors suggested that this could be due to the carbonic anhydrase activity of thiazide diuretics. 

Yes, I know that thiazides reliably cause metabolic alkalosis, but despite that they have some minimal carbonic anhydrase activity that is uncovered in the NCCT knockout mice. According to this site, thiazides were initially designed to be carbonic anhydrase inhibitors, and then found to have NCCT antagonism activity. (Fun fact if you ask google about the thiazide's effect on carbonic anhydrase the top hit is from David Goldfarb (@Weddellite) back from his basic science days.)

Back to the carbonic anhydrase story. Carbonic anhydrase is critical for bicarbonate reabsorption in the proximal tubule because it allows hydrogen secreted by the Na-H exchanger to combine with filtered bicarbonate to form CO₂ and water. The CO₂ is able to freely able to enter the proximal tubule cell where it combines with a hydroxyl group to reform bicarbonate. 

The authors concluded that by blocking carbonic anhydrase, there was less sodium reabsorption in the proximal tubule leading to activation of tubular glomerular feedback lowering GFR.

This lead to a second series of experiments where the same team reproduced the same reduction in urine volume but this time with acetazolamide, rather than HCTZ. The authors also thought there was a second mechanism based on acetazolamide's ability to decrease lithium entry into principal cells of the collecting duct (similar to amiloride) and/or a reduction in intra-renal prostaglandin synthesis.

Fast forward to November 2016 and we have an interesting letter in the NEJM regarding a human patient with NDI that was admitted for a craniotomy. Post-operatively he developed recalcitrant hypernatremia with severe polyuria rising to 12 liters a day. 

...we administered acetazolamide to a patient with severe lithium-induced nephrogenic diabetes insipidus that was resistant to hydrochlorothiazide treatment and other measures...

The team used 500 mg of acetazolamide bid to take his urine output from ridiculous to merely absurd. Compelling data.

What does a medical student do when they have a renal question? Introducing #AskRenal

Yesterday's post and interaction has been bouncing around my skull all day. First of all I was blown away by the discussion generated by the simple question of "What does aldosterone do?"

@niaree @kidney_boy Take a look at this summary, as well. Part of an epic review of the evolution of aldosterone. https://t.co/xILmMwHSeG pic.twitter.com/b4mdjIcOhn

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@niaree @kidney_boy Last paragraph of this review in Cell 1983 suggests that's not a new problem. Can be bought cheaper, I think, tho pic.twitter.com/XlAMgn9CiC

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@niaree Yes! You can request 'Hunger for Salt' be delivered for pickup at EHSLhttps://t.co/ZIKBkWnfSu

— Eccles Library (@EHSLibrary) December 8, 2016

And then I started to think about the possibilities. I imagine that Niaree has a lot of friends with nephrology questions. And I have a lot of friends that are nephrology nerds just bubbling with answers.

So what would happen if she introduced me to her friends and I introduced her to my friends

I'm thinking if there was a hashtag that could be used by medical students struggling with renal phys and renal pathophys that resulted in an immediate answer from nephrologists all over the world we could leverage the always-on nature of Twitter to demystify the black box that is the kidney.

Plus getting the pulse on the questions that keep hanging medical students will make us all better teachers.

So why don't we try this. 

Medical students brings us your confusion, your riddles, your frustrations with renal. Your mass of ambiguity yearning for clarity. Throw off your darkness for enlightenment. #AskRenal is here to clarify your journey.

No Salt Humans

Great Twitter moment tonight when a medical student confessed ignorance of aldosterone and an aldosterone basic scientist piped in with what he finds beautiful about aldosterone.

Renal Week 2: I'm still not sure what aldosterone does. Seems important, though! 🤔🤔

— Niaree Davis (@niaree) December 1, 2016

@niaree @kidney_boy Na is tiny&goes right thru glomerulus. Need means to effect controlled reabsorption or you'll be sodium-free in 2 hours😱

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@kidney_boy @niaree Signific of aldosterone highly dependent on sodium intake? Not sure Yanomami man could survive 5 mg lisinopril, ca 1970?

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

I had no idea what Yanomami man was but Brian was right there:

@kidney_boy @niaree Here's an old paper describing the Yanomami population that is interesting https://t.co/XzhZ1AGfTp

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

So the paper is available for free here and it shows a kidney homeostatic system performing in ways that I would have guessed were impossible.

A 24-hour urine sodium of 1 mmol. No fricken way!

I give you table 4:

Anybody want to hazard a guess at what the giant unmeasured anion in the urine is?
Phosphate?
Bicarbonate?
Probably bicarb, especially when you take a gander at their aldo levels:

I wonder if these indians suffered from all of the ill effects of aldosterone thrown about?

Treating mild hyperkalemia

Somewhere along the road to becoming a doctor med students develop the hyperkalemia insulin reflex. See an elevated potassium give 10 units of IV insulin and 25 grams of D50. Yesterday I saw this done for a potassium of 5.6.

No. One. Dies. From. A. Potassium. Of. 5.6.

But there is morbidity from the insulin glucose antidote.

These guys from Rush University Medical Center looked at the risk of hypoglycemia from the standard 10 units of insulin followed by 25 grams of glucose. They found 13% of ESRD patients developed a glucose south of 60 mg/dl.

Remember the kidney both metabolizes insulin and is a source gluconeogenesis, so dialysis patients are naturally more prone to hypoglycemia.

 Love me some table one.

The patients that developed hypoglycemia were less likely to be diabetic, and had a lower glucose. In response to this study the authors suggested an alternative regimen of increased glucose monitoring and an additional 25 grams of dextrose:

Similar data was found in a study by Schafers. Schafers followed that study with this one, which suggests that weight based insulin dosing 0.1 units/kg up to 10 units could reduce hypoglycemia by about half:

What is truly terrifying is if some people start trying to really drive the potassium down with Sterns' recommendations from KI:

Sterns suggests 6u bolus f/b 20u/hour insulin + 60 g glucose/hour for acute hyperkalemia in KI review https://t.co/vUTgibCyxE

— Swapnil Hiremath, MD (@hswapnil) April 14, 2016

Also good factoid, there is less hypoglycemia if you add albuterol to insulin and glucose.

Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects

Let's be careful out there and stop treating inconsequential hyperkalemia, let's save our toxic antidote for truly toxic potassiums.

At what potassium would you give insulin + glucose?

— Joel Topf, MD FACP (@kidney_boy) December 6, 2016