Author: Joel Topf

Posted on

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 ๐Ÿคช 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 wouldnโ€™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 Iโ€™d be interested to know how. #MedEd

Also, great study ๐Ÿ‘

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.

Hyponatremia-Gemini-TweetorialDownload

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.

Posted on

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?

Posted on

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.

Posted on

Download your Twitter Archive. Part 2

The destruction of Twitter seems to continue. Tweet threads like this do not make me optimistic about the future, so download your Twitter experience before Twitter.com is nothing more than a empty website.

After requesting your archive you need to wait for twitter to package up your experience. When they do you will see this on your time line

And this in your email

After I requested my Twitter Archive, it took two days for mine to be available. This is longer than I have seen in the past, makes me think there is a mad rush for the door and a lot of people are doing this.

When you click on the tweet it asks you for your password and then lets you download your Twitter Archive.

It can be a big file. Mine is 5.1 gigs. The archive it is a folder containing two other folders and a text file called Your Archive.html. Launch that and you will be greeted with this.

Clicking on “Tweets” allows you to see your entire history with a nice search function on the right.

Posted on

Download your twitter archive right now

I don’t know where Twitter is headed but it doesn’t seem good and I think in the next month or two (weeks?) there is a real possibility of going to twitter.com and seeing a blank page.

#NephTwitter has developed into a wonderful community and if Twitter disappears the community will be forced into a diaspora. NephJC has the podcasts, the newsletter, and the website to communicate our next moves. If you do not subscribe to the newsletter, now would be a good time to do so.

This coming Tuesday, November 15th, NephJC will be discussing EMPA-Kidney and after that discussion ends at 10pm we will be hosting a Twitter Spaces audio chat to discuss about what to do “After Twitter.”

In the mean time, if you have been investing in Twitter for a year, five years, ten years, fourteen years, then you should download your Twitter archive.

To do this go to your profile page and press “More” It will look like this.
Then click on “Settings and Support”

From “Settings and Support” Click on Your Account and then Download an archive of your posts.

Twitter will ask you for your password and then it will e-mail you a note when the archive ready to download.

Posted on

Adding more meetings to the meeting

Kidney Week is approaching. After a two year hiatus we are going to meet in person again in less than a month. I am very excited. NephJC and the NSMC will have a great presence and it should be fun.

You can take a peak at the line up here: #NephJC is going to be busy at #KidneyWk. Join us!

But I think ASN and the Kidney Week planning committee could be doing more to increase engagement. To make the event more fun.

I took a crack at it in this tweetorial

Modest proposal for @ASNKidney #KidneyWk.

Sunday is the least attended day of the conference. It is a half day and most people leave that morning and miss the whole day.

Sundayโ€™s Plenary session should begin at 9 not 8 to encourage people to go out and socialize Saturday night and to make room forโ€ฆ

7:30 AM Sunday have 5k run/walk. Do a different kind of social event. Raise money for a local charity. Let nephrologists form teams. @VUMCKidney team. @arkanalabs @goKDIGO all could have shirts and shared a moment.

These national meetings need to move past charging hundreds of dollars for slideshows and be more about being with your people.

Originally tweeted by Joel M. Topf, MD FACP (@kidney_boy) on October 12, 2022.

There are 41 sessions on Thursday.

41 on Friday

30 on Saturday

and 8 on Sunday

Adjusting the schedule on Sunday truly is a model proposal. I would love to see ASN try some new ideas at Kidney Week.

Posted on

Apology

I have an apology to make.

I spoke before thinking. I spoke loudly. I spoke and I hurt people. People who mean a lot to me. I hurt a mission that means everything to me.

I tweeted in anger and I said things to an imaginary place inside my phone that I would never say in person.  

I spoke without grace. I spoke with a foul mouth. 

We say it all the time, โ€œDonโ€™t Tweet Angry,โ€ and itโ€™s because we know the internet has a way of making us forget there are humans on the other end of the tube. In this case, the humans were people I know. People who are passionate, conscientious, dedicated, and good.  

This is bad. This is not who I aspire to be. I am sorry.

I hurt people that are contributing to this great collective, this great educational mission. #NephTwitter is the greatest FOAMed effort in Medicine. #NephTwitter is what every specialty in medicine should aspire to. And the Nephrologists running The GlomCon Fellowship are doing a great job building #NephTwitter. I should never do anything to tear this down. I am profoundly sorry. 

Letโ€™s keep AngryTwitter as far from #NephTwitter as possible.

I will start with myself. I will be better.

Posted on

An introduction to sodium and water

A number of years ago, I was invited to write a chapter introducing sodium and water for a new medical text book under the Scientific American brand. I remember being disappointed that I didn’t get hypo- or hypernatremia and being stymied for awhile before I figured out how I wanted to the topic. Ultimately, I had a great time writing the chapter and, at least at the time. I was quite proud of the work. The textbook was somehow abandoned somewhere between inviting the chapter authors and publication. The publisher pivoted to some online component that was supposed to rise out of the ashes of the text book and they asked me to do additional work. I never did that work and they never asked a second time, so I don’t know if that ever came to fruition.

Anyways, this chapter has been sitting in the bowels of my Google Drive for years.

I hadn’t thought about this until recording chapter seven of Channel Your Enthusiasm podcast where we are reading through Burton Rose’s classic Clinical Physiology of Acid Base and Electrolyte Disorders. In Chapter 7, Rose discussed using simple math to predict the changes in intracellular and extracellular fluid volume following various fluid and solute challenges. This is exactly what I did in my Scientific American chapter. I found the exercise to be a profound moment of understanding.

Here is a link to the Google Doc:

Google Doc

And a PDF of the same:

PDF

Posted on

A bit of NephMadness history

As I was spelunking in the depths of my hard drive I came across this document from the end of 2013. We had completed the inaugural year of NephMadness and after returning home from Kidney Week, Matt, Edgar, Kenar and myself put together a proposal to make NephMadness a recurring event.

It is remarkable that we were putting the pitch together in November and December when the contest would launch in March. Now NephMadness is a 9 month month process with planning usually beginning in June.

Some notes from the document. In 2014, we were still trying to figure out how to determine the winners. I love this paragraph, especially, “One down side of this is that it will make the contest appear rigged, which it actually is.”

I also like this part which gives you an idea of how small not only NephMadness was in 2013, but how small the footprint for online nephrology education was:

1. We were highlighted at the AJKD editorial board meeting to a geographically diverse, packed room. Dr. Levey asked how many people participated in the first NephMadness and almost no one raised their hand.

2. A day later we demonstrated NephMadness to a room of cutting-edge educators. I got the feeling, besides the usual suspects (Edgar Lerma, Pascale Lane, Tejas Desai, etc.) no one in the room had heard of the campaign. The crazy bit was, I donโ€™t think many had heard of PBFluids.com or NephronPower.com. This really reinforced to me how limited our exposure was. We had reached out to a lot of people and had dramatically boosted the traffic to the blog but to a large extent we were preaching to the choir.

And lastly, in the publicity section we were excited about getting featured on Dr. Mike Sevillas Podcast, which has since gone defunct after 372 episodes!

So here it is for all your NephMadness nostalgia needs…

NephMadness-2.0-PitchDownload
Posted on

Thoughts on the eve of the release of difelikefalinโ€ฆ

Iโ€™m in the taxi leaving #NKFClinical (or at least I was when I started writing this) and if it wasnโ€™t the first in-person meeting that most of us have been to since the onset of the pandemic, it would be remembered as “the one where Korsuva was launched.”

Room key and business cards from the Vifor Army at the meeting

During the meeting there was a buzz about this drug. And the buzz was around the two phase-3 trials, KALM-1 and KALM-2. The buzz is around the decreased effect size from KALM-1 to KALM-2. Difelikefalin met it’s primary endpoint to reduced severe itching in KALM-2, but the effect size is notably smaller than in KALM-1.

The results from KALM-1
The results from KALM-2

The effect size could have been larger, the same, or smaller than KALM-1. Iโ€™m not sure how much shade should be cast that it turned out to be smaller, especially as it remains better than placebo.

But my primary concern is that focusing on effect size misses the point. 

We are used to prescribing invisible drugs; drugs that move a magical end point like cholesterol or blood pressure. Lowering cholesterol does not make patients feel better it just loads the dice so that when fate rolls them every year your patient is less likely to have an acute MI. Same with antihypertensives, SGLT2 inhibitors and almost everything we use except for pain killers. If the patient asks the doctor if the drug is working it is an invisible drug. If the doctor asks the patient if the drug is working it is a visible drug.

I was a sight PI on KALM-1, which means I am one of the few nephrologists who has real world experience with the drug. During KALM-1 I saw people have remarkable response to study drug and I saw people people have no response to study drug. Since I was blinded, I assumed that everyone having a good outcome was on drug and everyone without a response was on placebo. That is always a fairy tale and I now know that wasnโ€™t true. Both KALM trials showed a big placebo effect (not as big as difelikefalen, but big). The placebo effect was large enough to convince me that all the success I have seen with diphenhydramine, gabapentin, steroid creams (none of which have robust supportive data), was likely just placebo effect. And now we are about to get the opportunity to switch everyone who has failed placebo to start an effective drug. But the wonderful thing is we do not have to just hope the drug is working, we can just ask our patients. Use it for a few months and ask people if they are better. No need to worry about the statistical effect size, all we need to do is assess the effect size in the patient in front of us. If the drug is not working stop the drug. However, be aware, a few weeks later the patient may tell you how much they liked it and that it was helping more than they recognized. My study patients were most vocal after the study concluded and everyone stopped study drug and went back to usual care. Multiple patients begged to enroll in extension studies, different investigations, anything to get access to difelikefalin…because uremic pruritus is miserable. 

Difelikefalin is the first drug we have in nephrology whose specific purpose is to alleviate symptoms. This is a different type of drug and we need to retrain ourselves to shift our view on effect side.

After I wrote this, I was made aware of two other anti-itching drugs that I was not aware of. I have no experience with them, but I thought I would list them here:

Nalfurafine a K-opioid-receptor agonist which is approved in Japanย (2009) and South Korea (2013).

ย Nalbuphine, a mixed k-opioid-receptor agonist and partial-opioid antagonist. It has central nervous system effects and may cause dysphoria. It has abuse potential, though it was initially a schedule II drug, it no longer is.

COI: I was a site PI for KALM-1. I recorded a video testimonial for difelikefalin a few years ago. I have attended an advisory board with Cara, the company who developed the drug. I have participated in these because I have seen the product relieve suffering. I would not support a product I did not believe in.