Author: Joel Topf

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Adrenal insufficiency and hyponatremia

Every intern knows that the evaluation of hyponatremia includes a TSH and a cortisol level to rule out hypothyroidism and adrenal insufficiency as occult causes of euvolemic hyponatremia.

The mechanism of adrenal insufficiency is a bit confusing with some sources stating that these patients are volume depleted while others are euvolemic.

In some patients without aldosterone, the patients develop severe salt wasting, become hypotensive and get a non-osmotic release of ADH resulting in hyponatremia. These patients will respond to saline. Treat the hypovolemia and the sodium will go up.

Hyponatremia is a common manifestation of adrenal insufficiency even in cases without adrenal crisis. Giving saline to these patients is not effective at correcting the hyponatremia. Giving cortisol, however, results in a brisk water diuresis and rapid correction of the serum sodium (Oelkers, NEJM, 1989).

In addition to being resistant to saline, ADH antagonists (think tolvaptan) protect against this type of adrenal insufficiency-induced hyponatremia.

This means cortisol corrects an abnormality that is due to excess ADH. 

Here is the explanation from the late 90’s from The Fluid, Electrolyte and Acid-Base Companion. 

Bartter and Schwartz original definition of SIADH required a normal cortisol specifically to exclude patients with hypopituitism and primary adrenal insufficiency. In primary adrenal insufficiency, in addition to loss of cortisol there is an aldosterone deficiency which can result in sodium wasting, volume depletion and a non-osmotic (decreased perfusion in this case) stimulates for the release of ADH. In this scenario, the patient should appear salt/volume depleted and would not be considered euvolemic.

A nice review of secondary adrenal insufficiency and hyponatremia was done by Sven Diederich.

Remember:

  • Primary adrenal insufficiency: destruction of the adrenal glands leads to loss of endogenous cortisol. These patients typically also have aldosterone deficiency, so they will be salt wasters, resulting in hypovolemia. They will also have hyperkalemia.
  • Secondary adrenal insufficiency: decreased ACTH (from pituitary or hypothalamic disease, or from pharmacologic steroids) prevents secretion of cortisol

In Diederich’s review they pulled 139 cases of hyponatremia that were referred to endocrinology. (Clearly this study suffers from profound selection bias. Here is a a cleaner study on the epidemiology of hyponatremia by Schrier, from back in the day.) They found 28 cases of hypopituitism leading to hyponatremia. Patients tended to be older (average age 68) and more female (75%). In 25 cases the hypopituitism had not previous been diagnosed and 12 patients had previously been admitted (between 1 and 4 times) for severe hyponatremia without an adequate diagnosis.

Basal cortisol levels were as follows:

  • Below 100 nmol/L (3.6 mcg/dL) in 7
  • Below 200 nmol/L (7.2 mcg/dL) in 21
  • The mean level was 157 nmol/L (5.7 mcg/dL)
  • The highest basal level was 439 nmol/L (16 mcg/dL)

Imaging results:

  • Twelve patients had an ‘empty sella’
  • Six patients had pituitary tumors

  • One had secondary adrenal insufficiency due to chronic treatment with prednisolone because of ankylosing spondylitis

Don’t be the doctor that corrects the hyponatremia but fils to diagnose adrenal insufficiency and discharges and sends the patient home only to redevelop hyponatremia another day. Turn over every stone, especially in patients with SIADH of undetermined etiology.

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The mentor keynote

Matt Sparks gave KidneyCON keynote on Friday night. It was an amazing talk.

Things you don’t see at #KidneyWK

John Arthur asked Matt to talk about his career and how he navigated medicine to become an accomplished scientist, clinician, and educator.  Matt organized his talk around the mentors that guided him. The theme was that the way he made his way forward was by finding the best mentors available and learning as much as he could from them. It started with Wynton Marsalis

Though he went to the University of Arkansas to play trumpet he transitioned to biomedical science and found Dr Jeannine Durdik, an inspiring basic science professor, who taught him the scientific method.

After flirting with a career in basic science he went medical school at the University of Arkansas and matched at Arkansas where also did a chief resident year. The chair of medicine was Dr. Andreoli. I never knew Andreoli, but he sounds like the type of physician they don’t make any more…and you are simultaneously saddened and relieved by that fact. Andreoli was a giant in nephrology and Sparks worked close with him as a resident and closer during his chief year.

Andreoli directed Matt to Duke where he mentored by Tom Coffman. Coffman taught Matt how to write and directed him on his scientific career.

Then Matt talked about going to Mount Desert Island and meeting Nate Hellman. Matt was already an avid reader of the Renal Fellow Network, and Nate invited Matt to contribute. Matt really didn’t get involved until after Nate passed away and this ignited his desire to contribute to the Renal Fellow Network. This is how Matt got involved in and ultimately helped forge what would eventually become our online tribe of nephrologists.

It was fascinating to see the people that mentored Matt, because he is a mentor to so many right now.

Matt seems to know every nephrology fellow in the country and he takes an interest in promoting them and getting them involved. He is a strong advocate for fellows, both in and outside of Duke.

Even though Matt is younger than me, he is one of my important mentors. He has a wisdom that I don’t have and I often go to him with questions. I also trace my success with social media to his reaching out to me back in 2010. He guided me and really transformed my efforts from a solo project to one that recognizes that we can go further and do better by working together. Its a simple lesson but it has been critical to all of the successes we have found in social media.

Matt,

Congratulations on the Keynote.

Congratulations on putting together an amazing conference.

I am honored to be your friend and mentee.

Joel

 

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#KidneyCON Fluid, Electrolyte, and Acid-Base Workshop

David Goldfarb (@weddellite) and I put on a fluid, electrolyte and acid-base variety show at KidneyCON. The itinerary:

  1. IV fluid taste test
  2. Hypernatremia
  3. Management of calcium phosphate stones: to K-Citrate or not?
  4. Management of chronic hyponatremia, use of DDAVP
  5. Aspirin toxicity
  6. Hyperkalemia

Both of us had a bunch of additional cases that we didn’t get to so be sure to go deep into the presentation files.

Here are the presentation files:

 

 

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The Swami goes 4 for 8 and is looking for a new job

The Effluent Eight for #NephMadness are out and The Swami is not looking so hot.

Let’s break it down by region

Women’s Health Region

Swami’s Pick: Menopause and CKD

Blue Ribbon Panel’s Pick: Reproductive Planning

I still like my pick. Menopause in CKD is so poorly understood and it affects so many more people with CKD. I think this is a #BlueRibbonFail

Animal House

Swami’s Pick: Shark Maintenance of Osmolality

Blue Ribbon Panel’s Pick: Camel Water Storage

I went with what I thought was the crowd favorite, shark. This is a case where the blue ribbon panel dug in to the science and I just waved with the crowd. #SwamiSucks

Peritoneal Dialysis Region

Swami’s Pick: Volume Control in PD

Blue Ribbon Panel’s Pick: Volume Control in PD

A win.

Trial Outcomes Region

Swami’s Pick: 40% Reduction in eGFR

Blue Ribbon Panel’s Pick: Patient Related Outcomes

Interesting pick by the BRP. I can see the logic. Fair choice.

Hyponatremia Region

Swami’s Pick: US Guidelines

Blue Ribbon Panel’s Pick: US Guidelines

Another win. Two for five would get me in the Hall of Fame if I was up against major league pitching. I’m not.

Contrast Region

Swami’s Pick: Contrast is nephrotoxic

Blue Ribbon Panel’s Pick: Contrast in CKD 4

Not sure I understand the logic here. If you really think contrast is nephrotoxic, don’t you need to double down and take it over Contrast in CKD 4? If you giving contrast to a patient with a GFR of 16 ml/min, you really don’t think it’s nephrotoxic, now do you?

Pediatric Nephology Region

Swami’s Pick: Genes in CAKUT

Blue Ribbon Panel’s Pick: Genes in CAKUT

Michelle should have listened to me.

Transplantation Region

Swami’s Pick: The Untransplantables

Blue Ribbon Panel’s Pick: The Untransplantables

Nailed it.

So The Swami goes 4 for 8. Not bad, but not good enough. Thinking about moving this crystal ball on e-bay.

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Is estimated GFR racist?

Update from January 2021: This is an old post and I have evolved my thoughts on this issue. I leave this here mainly as bread crumb on the trail of my evolving thoughts about this topic.

 

 

Zachery Berger published this epic tweet storm last week about estimated GFR. It starts here:

The conclusion is that using race in the MDRD formula (and by extension the  CKD-epi formula) is inherently racist.

I do not think this is the case. Trying to estimate GFR from a serum creatinine and a few demographic variables is impossible, the best we can hope for is a reasonable guess. To see how bad we are take a look at the wide variability at high GFRs with the current CKD-Epi formula:

So that GFR of 60 has a 95% CI of being between 35 ml/min and 92 ml/min. Not so reassuring.

One of the primary reasons for this imprecision is that creatinine production varies from body to body. When one person produces more creatinine than another, for a set rate of creatinine excretion his serum creatinine concentration (what we measure on a blood test) will be higher. Who produces more creatinine? People with more muscle mass.

  • Larger people produce more creatinine than smaller people
  • More muscular people produce more creatinine than less muscular people
  • People with four limbs produce more creatinine than people with 3 limbs
  • Men produce more creatinine than women, on average
  • Young people produce more creatinine than older people, on average
  • Vegetarian Indians produce less creatinine than westerners
  • Black people produce more creatinine than non-black people, on average

The data is shown in figure 1 of Levey’s 1999 study.

Even though Dr. Berger did not draw the conclusion that estimated GFR is inherently sexist, let’s look at gender first. I have recolored the two graphs and superimposed them on one another. Men are in red and women are in blue:

It is clear that for any given GFR the men tend to have a higher creatinine than the women. This is not perfect and it is not hard to pick out individuals where this generalization fails, but in general this is a fair generalization. Levey comments and quantifies this gender difference:

At any given GFR, the serum creatinine concentration is significantly higher in men than in women (P 0.001).

The figure, without any recoloring, provides the curves for black (solid line) compared to non-black (dotted line) patients. Again it is clear that the average GFR is higher for black patients at any set creatinine. Levey comments and quantifies the racial difference:

At any given GFR, the serum creatinine concentration is significantly higher in men than in women and in black persons than in white persons (P=0.001).

Dr. Berger misses this fact:

How do we know *that* to be true? BECAUSE THEY MEASURED IT!

The refernces are just there to show that this is not a new and novel finding. This was an expected finding. The study does not rest on these references. The investigators in the MDRD study measured the serum creatinine, GFR, and asked patents if they were white, black or hispanic. The data shows that black people had, on average, 18% higher GFR for any measured creatinine. The fact that the prior work on this subject was deplorable does not alter the findings.

Berger is so upset that the estimated GFR differentiates black and white people that he misses the real problem with the MDRD study, the embarrassing lack of black people in the original data set. Only 12% of that cohort was African American, less than 200 people. A group that has the greatest incidence of end-stage kidney disease should be over-represented in a study about reducing the progression of CKD, not under-represented. Remember, Levey was using the data already collected for the Modification of Diet on Renal Disease study. This was not de novo data collected for the purpose of generating this equation. This weakness was corrected in the CKD-Epi equation where there were nearly 3,000 African Americans representing 30% of the cohort. The adjustment for race went from an 18% bump in GFR for a given creatinine down to 15.9%. Not much difference.

We use race, gender, and age not because we are racists, sexists, and agists, but rather because there are physiologic differnces between the races, the genders, and the aged. We exploit those differences to improve the accuracy of our estimate. All of these adjustment are just attempts to use demographic variables to squeeze a better correlation of GFR from a serum creatinine.

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You knew that proteinuria is protective against amphotericin induced hypokalemia. Right?

All of you #NephMadness players crying into your coffee about Proteinuria getting beat out by Patient Reported Outcomes need to understand that proteinuria isn’t always bad*.

*I am being sarcastic here, proteinuria is always bad, and the only reason I am writing this post is because of this interesting quirk where it appears to be protective.

Proteinuria protects against amphotericin b induced hypokalemia. In patients on amphotericin, heavy proteinuria, a protein concentration of 3 g/L (3+ on dipstick), is protective against amphotericin b induced hypokalemia.

The study was done on normal formulations (as opposed to liposomal preparations) of amphotericin B.

Amphotericin B is highly protein bound. With standard doses, the normal amphotericin concentration in the urine will be 1-2 micromol/L. With 3+ urine protein, the albuminuria concentration is over 40 micromol/L, and this is apparently enough to bind and neutralize amphotericin’s collecting duct toxicity. Amphotericin’s anti-fungal property comes from its ability to tear open fungi cell membranes. Unfortunately it does a doozy on the membranes of the collecting tubules as well, allowing potassium to flow down its contraction gradient from the cells to the tubular fluid (and out in the urine). Similarly hydrogen flow from the tubular fluid back into the cells causing metabolic acidosis. It is an unusual cause of renal potassium loss without increased aldosterone levels.

For you #NephMadness geeks, toad bladder was instrumental to working out the mechanism for amphotericin induced hypokalemia.

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Swami is clairvoyant

The Saturated 16 has been announced and 6 of 8 of the Swami’s Regional champ predictions are still alive.

The two misses: Menopause and Shark. Menopause got crushed by the Blue Ribbon Panel and the crowd. I guess we now know why there is so little research on this.

The Swami had Menopause going deep so this is going to hurt.

Shark not making the cut? I have no words.

But with 6 of 8 still alive The Swami looks forward to the coming apologies…

https://twitter.com/poyanmehr/status/979121802650759168?s=21

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I am The Swami of #NephMadness let me build your brackets and fill your pockets

Student loans…credit card debt…car payments

I can make them all disappear.

In previous years I couldn’t prognosticate on NephMadness because I was contaminated by running the Blue Ribbon Panel. This year I have have no such inside knowledge. I am free and I am going to share the wisdom I have gained by running the previous BRPs to give you can’t-miss-locks.

In previous years there has always been prohibitions from any type of gambling

But in 2018, AJKD forgot to ban gambling. So call your bookie! Mortgage the house! Cash in the kids’ 509 college plan! I’m going to whisper the winners. These darlings are your chance for a better life!

 

We are going to skip the Satuated Sixteen and go right to the regional champions.

The Effluent 8:

Women’s health

Menopause is the dark horse here. Everyone is going to go with reproductive planning because when a dialysis patient gets pregnant everyone goes crazy. But the issue that affects almost all of our female patients is menopause. This is seriously under-studied and it’s going to cut throught this region like a knife through butter. This is a bracket buster and when it beats reproductive planning on March 31st, #NephTwitter is going to be out for blood. You won’t be crying because your going to pick menopause right now.

Animal House

No bracket busters here. This is going total chalk. Pick Shark like everybody else. Getting cute with camel or toad is just going to make you poor. Shark FTW.

Peritoneal Dialysis

This is going to be a tough call, and I’m worried that the Blue Ribbon Panel could make a mistake here and foolishly go with PD catheter dysfunction but the answer is Volume Issues. Volume Rules.

Trial Outcomes

This one is easy. It is 40% drops in GFR. Nephrologists have been telling people not to perseverate over the creatinine for years. We told them eGFR was a better estimate than any serum creatinine. We have been calculating eGFRs for 20 years. The fact that the FDA is still looking at doubling of creatinine is a travesty. An eGFR based trial outcome is long overdue. 40% loss of eGFR destroys this division to advance to the Elite 8.

Hyponatremia

The US Guidelines are a juggernaut. Ignoring the placebo-controlled trials supporting Vaptans while prescribing your patients urine pills supported by a few observational trials is knocking on homeopathy’s door.

Contrast

NephMadness is innovative but there is no way nine nephrology leaders are going to go on the record and say contrast is not nephrotoxic. This is easy, Contrast is Nephrotoxic cruises to the win here.

Pediatrics

Genes in CAKUT. There are no pediatricians on the BRP. They are going to go full science when faced with this question. Don’t doubt me. This one is a lock.

Transplant

The Untransplantables is going to win this one. Best name. Best science. No contest.

The Filtered Four

Menopause versus Shark

Animal House was fun, but up against Women’s health it will be treated as the gag region that it was meant to be. Menopause walks all over Shark. Sorry.

Volume issues versus 40% drop in eGFR

Redefining the primary outcome of every major CKD study for the next 20 years is going to be unstapable. 40% drop in eGFR FTW!

The US Hyponatremia Guidelines vs Contrast is Nephrotoxic

My crystal ball gets a little cloudy here. Guidelines are a little dull and the BRP may not want to advance them to the Filtered Four, but at the same time, I suspect they will be looking at how thin the data on contrast being actually nephrotoxic and will feel a bit guilty. The US Guidelines advance here.

Genes in CAKUT vs The Untransplantables

No contest. The peds topic is dropped like a dirty diaper. The Untransplantables advance

The Filtered Four

Menopause vs 40% drop in eGFR

This is the year World Kidney Day was devoted to women’s health. Menopause takes that momentum and rolls over Drops in eGFR of 40%.

US Guidelines vs The Untransplantables

The US Guidelines have navigated to the final four by finding a weak stream of competitors. They have no reason to be there. They are The Loyola Ramblers and Sister’s Jean’s run is about to run out. The Untransplantables rips up the guidelines.

The Left and Right Kidney

Menopause versus the The Untransplantables

Everyone loves transplant, and transplant always wins.

Your NephMadness champion will be The Untransplantables.

Now get to Tourneytopia and register to play NephMadness…Time is running out.