E-mail from my first trip to Kidney Week

My wife and I celebrated out eighteenth anniversary last night. We went to dinner in Windsor. While we were in line waiting to cross back into the US, Cathy found and read some of our e-mails back and forth from the first few years of courtship.

Here is one that I sent from my very first first trip to Kidney Week, which wasn’t even called that back then.

From: Joel Topf
Date: October 25, 1998 at 2:59:00 PM EST
To: Cathy
Subject: I met my hero

Cathy, the conference is awesome. I’m having fun.

I just met Burton Rose. He’s the reason I’m going into nephrology. It was a moving experience.

I’ll call you later
love you
always
j

June 19, 2018June 28, 2018

The MM4MM video. Gives me goose bumps

June 16, 2018

Hyponatremia fan fiction

I think I may have buried the lead in the last blog post. Perhaps this imaginary conversation will clarify what is so important about the George et al study.

Nephrologist: There are now clinical practice guidelines, based on expert opinion, that tell us to correct sodium no more than 8 mmol/L in the first day of hyponatremia.

Internist: That seems cautious. How well are we meeting those guidelines?

Nephrologist: Well in a recent multi-center, retrospective analysis, of nearly 1500 people with an initial sodium below 120, just over 40% went too fast.

Internist: FORTY PERCENT were too fast. Oh my god! We’re doing horrible!

Nephrologist: Yeah, it’s kind of embarrassing.

Internist: So what happened to the 600+ people where the speed limit was exceeded?

Nephrologist: Well, they found 9 people had osmotic demyelination on MRI. But none of them had any documented permanent neurologic deficits and none of them was diagnosed with central pontine myelinolysis.

Internist: So how many people could we help if we worked on protocols, education and training to get that 40% closer to 5 or 10%?

Nephrologist: Well, since with a 40% miss rate we couldn’t find any harm, I guess we couldn’t expect much improvement with a 5 to 10% miss rate.

Internist: We should probably put our energy elsewhere.

June 16, 2018

New hyponatremia data part 2.

This second article in the hyponatremia data dump comes from CJASN and like yesterday’s post, attempts to clarify who develops rapid correction of hyponatremia.

The U.S. Hyponatremia Guidelines (Verbalis, et al) recommend a speed limit for correcting the sodium of no more than 8 mmol/L in any 24 hour period for patients at high risk of osmotic demyelination (ODS). High risk is defined as anyone with:

Na < 105 mmol/L
Hypokalemia
Malnutrition
Liver disease

One of the items I hit home on in my lectures on hyponatremia is how rare osmotic demyelination actually is. I came to this conclusion when NephJC discussed The European guidelines on hyponatremia. The guidelines review every published case or case series of ODS from 1997 until 2012. Over those 15 years they found 53 cases world wide (See Appendix 6, Sheet 13a). Every year, in the US alone, there are around a million people who develop severe hyponatremia (Na < 126). With that type of denominator, 53 cases seems laughably small.

I have never seen a case of osmotic demyelination syndrome. I have seen a lot of mismanaged hyponatremia.

Never have so many, done so much, to avoid a complication seen by so few.

George, Zafar, Bucaloiu, and Chang analyzed the 7 hospitals in the Geisinger Health System to look at the incidence and risk factors for rapid sodium correction and osmotic demyelination.

They included adults with an initial sodium less than 120 mmol/L.

Their primary endpoint was an increase in sodium of more than 8 mmol/L in the first 24 hours.

Looking at the methods, it was not clear to me how they dealt with patients with multiple admissions for hyponatremia. Were they included multiple times? Did they only include the first admission?

They manually looked through every MRI report that was done after the index sodium to look for reports of ODS.

Results

They found 1,490 cases of severe hyponatremia with complete data that matched their inclusion criteria.

Median change in sodium in the first 24 hours was 6.8 mmol/L.

606 (41%) patients broke the speed limit of 8 mmol/L in the first 24 hours.

Risk factors for rapid correction

The authors provided a lot of depth on the risk factors for rapid correction. Here is the unadjusted risk factors.

Demographic:

Younger (average age of rapid correctors was 63 versus 68 in slow correctors)
Current smokers (40% of rapid correctors were smokers versus 26% of slow correctors)
Female gender

Medical history:

Depression (in 20% of rapid correctors versus 16% of slow correctors)
Schizophrenia (in 4% of rapid correctors versus 1% of slow correctors)
No history of hyponatremia (in 59% of rapid correctors versus 73% of slow correctors)
No history of chronic liver disease (in 6% of rapid correctors versus 8% of slow correctors)
No history of congestive heart failure (in 12% of rapid correctors versus 19% of slow correctors)
No history of cancer (in 19% of rapid correctors versus 25% of slow correctors)

Clinical data:

Lower body mass index (BMI of 26 in rapid correctors versus 28 in slow correctors)
Lower initial sodium (115 in rapid correctors vs 117 in slow correctors)
Lower initial urine sodium (35 in rapid correctors vs 43 in slow correctors)
Lower initial urine potassium (27 in rapid correctors vs 32 in slow correctors)
Lower initial urine osmolality (270 in rapid correctors vs 369 in slow correctors)
Have seizures (13% in rapid correctors versus 9% in slow correctors)

They used three different models for multivariate analysis to generate odds ratios for rapid correction of hyponatremia.

Some comments about the risk factors. I suspect the reason that depression actually represents SSRI induced SIADH that rapidly corrects when the drug is withdrawn. The schizophrenia association may represent psychogenic polydipsia, a common manifestation of schizophrenia. Water restriction will result in prompt normalization of the sodium.

Liver, heart, and cancer are all associated with difficult to treat hyponatremia, so no surprise that they saw lower rates of rapid correction among people with those diseases.

The lower BMI and female gender association with rapid correction may be simply due to lower total body water making these patients more susceptible to rapid changes in serum sodium.

Lower urine sodium may indicate patients with volume depletion hyponatremia, a population predisposed to rapid correction of hyponatremia as soon as the volume depletion is corrected, releasing the hypothalamus from the volume stimulated release of ADH and resulting in rapid drop in ADH and rapid, uncontrolled correction of hyponatremia.

The lower urine osmolality likely represents patients with psychogenic polydipsia, tea and toast syndrome, or patients who are already in the midst of spontaneously correcting their sodiums, all patients who will rapidly correct their sodium.

The people who are seizing are a cohort with, presumably, acute symptomatic hyponatremia and rapid correction is less problematic.

Osmotic demyelination syndrome

There were 295 patients who had an MRI after having severe hyponatremia. Nine had radiologic evidence of osmotic demyelination. No patients had an ICD diagnosis of central pontine myelinolysis. One patient had MRI evidence of ODS prior to correction of the sodium. Consistent with medical consensus, nearly all of the patents with incident ODS had rapid correction of hyponatremia:

Of the eight (0.5%) patients who developed incident osmotic demyelination, seven (88%) had documented sodium correction > 8 mEq/L during any 24-hour period before brain MRI.

The one patient with evidence of ODS without rapid correction of hyponatremia had been admitted within a month with a sodium of 105. So it is possible the ODS occurred with that episode rather than the one captured in the study.

The authors listed the characteristics of the patients with ODS:

Hypovolemia in 75%
Beer potomania in 63%
Outpatient thiazide diuretic use in 25%
Alcohol use disorder 50%
Malnutrition in 50%
Hypokalemia in 63%

Having hypovolemia in 75% and beer potomania in 63% means that some patients had to have both of these diagnosis. This portrays a misunderstanding of what constitutes beer potomania. Beer potomania induced hyponatremia is not merely a patient who drinks beer and develops hyponatremia, instead it represents a patient who is unable to clear the water volume in beer due to inadequate solute intake. These patients have maximally dilute urine. On the other hand, patients with volume induced hyponatremia are unable to clear excess water because of hypovolemia-induced ADH release. In one case you have high ADH activity and concentrated urine (volume depletion) and in the other case you have suppression of ADH and dilute urine. There can not be a meaningful combination of the two disorders.

Alcohol use, malnutrition and hypokalemia are all previously recognized risk factors for ODS.

Three patients had received 3% saline for acute neurologic symptoms of hyponatremia. This is critical information because it shows that just because someone has acute manifestations of hyponatremia and an indication for 3%, one must still pay attention to the speed limit. Often acute neurologic symptoms of hyponatremia is thought to indicate a failure to have compensated for chronic hyponatremia and therefore protective against ODS. This is not the case.

The finding that I found most interesting was the clinical outcomes of the patients with ODS.

Five patients with documented osmotic demyelination had recovery with no neurologic deficits, two patients died from unrelated causes, and two were lost to follow-up.

They had 9 cases of ODS and they weren’t able to document even a single case of neurologic devastation. Five of the cases had documented neurologic recovery. This is how Burton Rose describes ODS:

And here is how Sarah and I described it in the fluids book

In my mind if you don’t spasmodic, mirthless laughter you don’t have ODS.

This is consistent with a previous study of dialysis patients with hyponatremia who developed similarly clinically invisible ODS was diagnosed by MRI. From the discussion of Tarhan et al.

Contrary to its classic description, osmotic demyelination syndrome may develop without any presenting signs and symptoms in patients with end-stage renal disease who have undergone recent hemodialysis.

This largely asymptomatic ODS likely explains why not one of the 9 patients had an ICD diagnosis of central pontine myelinolysis (CPM). They did nt have any of the clinical manifestations of CPM.

When I read the abstract and saw that they had 9 cases of ODS in their cohort I jumed out of my shorts. This would be the largest series of DS ever. After reading the study I realize that actually we are in a new era of hyponatrmia where ODS can be devastating (read the three case reports in Brunner et al’s prospective study of MRI evaluation, PDF available on SciHub) or asymptomatic.

June 15, 2018June 15, 2018

New hyponatremia data

In the last couple of months there has been an outpouring of new hyponatremia data and resources. The first I want to discuss is data on the speed of sodium correction with tolvaptan.

Juan Carlos lead a group who looked at the speed of sodium rise with tolvaptan. The primary endpoint was the change in sodium at 24-hours in patients given 15 mg of tolvaptan.

All patients had to have failed fluid restriction to be included in the analysis.

For the purpose of the study, SIADH was defined as:

serum sodium concentration ≤ 130 mEq/L
serum osmolality ≤ 280mOsm/kg
urine osmolality > 100 mOsm/ kg
urine sodium excretion > 20 mEq/L

CHF induced hyponatremia was defined as:

serum sodium concentration ≤ 130 mEq/L
serum osmolality ≤ 280mOsm/kg
echo- cardiographic evidence of systolic or diastolic dysfunction
urine sodium excretion < 20 mEq/L (if not on diuretics)

All patients had to start with a tolvaptan dose of 15 mg.

The only other concurrent therapy allowed was fluid restriction. Patients who subsequently were started on D5 water, diuretics or salt tablets, had their data censored at the point where the additional therapies were added.

Diuretics are listed as an exclusion criteria but the CHF group were allowed to use them (an exclusion to the exclusion criteria). This is not well described in the methods.

Except for the half of the cohort that has heart failure.

After restricting the patients by their pre-specified exclusion criteria they had 28 patients with SIADH and 39 with CHF.

Table 1.

Remember how the urine sodium is supposed to be low in heart failure. Take a look at the elevated level found in this study. Conclusion: diuretics work. Also take a look at the low Bun and low uric acid in the SIADH group. These are really helpful in my experience at differentiating the cause in tricky cases.

Tolvaptan was much more effective in SIADH with an average change sodium of 0.80 mmol/L/hr versus 0.17 mmol/L/hr in CHF

Sodium went up by more than 12 mEq/L in 25% of patients with SIADH and 3% of patients with CHF.

Using linear mixed-effects models to conduct multivariable repeated-measures analysis the investigators found:

In SIADH a lower serum sodium (<120 mmol/L) and lower serum urea (<6 mg/dL) were risk factors for rapid correction of sodium.
In CHF, only serum urea was a risk factor for rapid correction

This is what these variables look like when mixed together (data for SIADH patients)

The discussion includes this tidbit where the investigators try to explain why there is a more dramatic response in SIADH than in CHF.

As seen in Table 1, average kidney function of patients with SIADH was significantly greater than that of patients with CHF. As shown in Figures 4 and 5, a total of 8 of 39 patients with CHF and 1 of 28 patients with SIADH had serum creatinine concentrations > 1.5 mg/dL. Thus, difference in kidney function may account for the observed difference in therapeutic response between the SIADH and CHF groups.

I don’t find this argument convincing because kidney function was tested to see if it predicted response and though eGFR did correlate with response to tolvaptan in SIADH, it was not an independent predictor of response and was not a predictor of response at all in CHF.

In the SIADH cohort, age and baseline values for serum sodium, serum osmolality, SUN, serum creatinine, MDRD, and CKD-EPI significantly correlated with the magnitude of increase in serum sodium concentration during the first 24 hours of therapy. Unlike those parameters, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either body weight, body mass index, or baseline urine sodium, urine osmolality, serum uric acid, or serum potassium value. In the CHF cohort, baseline serum sodium, serum osmolality, SUN, serum creatinine, and serum potassium values significantly correlated with the 24-hour increase in serum sodium concentration. Conversely, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either age, body weight, body mass index, or baseline urine sodium, urine osmolality, MDRD, and CKD-EPI values.

This article is accompanied by an editorial by NephMadness Selection Committee member Richard Sterns. He does a nice job describing why this rapid increase in sodium in SIADH show in Morris’ paper was not also seen in Schrier’s SALT 1 and 2 paper. In that phase 3 trial that lead to the approval of tolvaptan, there were 51 patients patients with SIADH, and only 3 of them corrected too fast. This is 6%, well below the 25% found in Morris’ study. Sterns points out the relatively high sodiums found in SALT study (no one below 120 and only 30 had a sodium below 130) as a likely explanation.

Sterns wraps up his editorial with a neat description of the pharmacokinetics of tolvaptan and arguing for dosing the drug at 3.75 mg and then repeating the dose as needed every 6 hours to titrate the change in the sodium level. Clever.

The minimally effective tolvaptan plasma concentration to increase urine output is approx. 25 ng/mL, and maximal increases in output occur when tolvaptan concentrations exceed 100 ng/mL. Levels > 25 ng/mL are achieved by doses as low as 3.75 mg, but do not remain at this level for long because the half-life for this dose is a little more than 4 hours. A 15-mg dose achieves peak plasma concentra- tions well above 100 ng/mL in patients with SIADH, enough to sustain a maximum water diuresis for more than 4 hours. A maximum water diuresis can increase the serum sodium concentration by >2.5 mEq/L per hour, yet it is not clear why this would be desired.

The standard practice in the United States is to administer 15 mg of tolvaptan and then encourage water intake to offset the resulting variable (and often large) water losses. Considering the high price of the drug in the United States (w$300 per tablet), this practice is basically flushing money down the toilet…

…A much more desirable outcome in patients with severe hyponatremia would be a modest but sustained increase in urine volume with a resulting slow steady increase in serum sodium concentration. If urine volumes were less massive, free-water restriction could be continued to avoid unwanted exacerbation of hypona- tremia. Theoretically, the desired response could be achieved with initial doses of 3.75 mg, repeating or increasing the dose every 6 hours if necessary, based on results of urine output and/or serum sodium levels measured before each dose, until the target increase in serum sodium level for the day is achieved.

Another source of additional insight on the study is an interview by Tim Yau of Juan Carlos at AJKDbog.org.

June 9, 2018

The Stanford short course on medical informatics, circa 1995.

After I graduated Medical School, I went to Stanford for a one week course on computer informatics. It was 1995. I had seen the world wide web before but this was my first exposure to HTML editing. We were shown expert diagnostics systems and an electronic medical record. It was Tomorrow Land for how the computer was going to shape the future of medicine.

The class was organized by Edward Shortliffe, At the time he was famous for this textbook:

It was published in 1990 and a number of our lectures came from chapters in this book. We think of the computerization of medicine as being a very contemporary subject, but Shortliffe was a co-author of a book titled “Readings in Medical Artificial Intelligence. The First Decade,” published in 1984!

The most important thing that I experienced in that course was Bayesian logic. There was a whole day on computer-aided diagnosis and as part of this, there was a lecture on the mathematics of pre-test and post test probability. Learning that there was a mathematical way to make sense of the uncertainty that had been a consistent companion on the wards was a revelation. I had travelled across the country to Palo Alto and Dr. Shortliffe had pulled the curtains of confusion from my eyes. He had shown me the science of medical decision making. It was a revelation.

At that time I was carrying around an HP200 lx, 1990’s ubercalculator/PDA.

It had an amazing programable calculator. I entered the equations for post-test probability and after class excitedly went up to Dr. Shortliffe and explained that I was sure that I could research the sensitivity and specificity of all the tests I needed, but I had never come across any data on the pre-test probability. I wanted to know where I could find that information. He looked at me and told me that the pre-test probability is your intuition as a doctor. You had to assign your own pre-test probability based on your history and physical and other pieces of data.

Intuition…

This detailed lecture with mathematical certainty was at its very core just human, fallible, intuition.

It crushed me. Math wasn’t going to save me.

I hadn’t thought of that moment in my medical education journey until I read The Laws of Medicine. Law 1: A strong intuition is much more powerful than a weak test.

Get a copy of this book and read it, so you can discuss it with #NephJC in the Summer Book Club this August.

June 1, 2018

Happy Birthday PBFluids: A decade of Blogging.

Me: PBFluids turns 10 years old this month.

Wife: You going to throw a party?

Me: No, but I’m going to write a blog post.

May 30, 2008, my first post at PBFluids.

Ten years. That’s a long time in career. At the speed of social media, it’s an epoch.

Defining moments from PBFluids’ first 10 years

The Beginning

When I started PBFluids, the there were two other nephrology blogs out there, Joshua Schwimmer’s Kidney Notes (March 7, 2005!) and Nathan Hellman’s Renal Fellow Network (Nate started his 5 weeks before PBFluids). Comparing PBFluids to Renal Fellow Network feels a bit like saying between me and Michael Jordan we have 6 NBA championships. But nonetheless, ten years ago we were the first few pebbles which started rolling down this mountain which has become an avalanche of online nephrology education.

Though there was Nathan and Schwimmer, and a year later Kenar (December 7, 2009, talk about a day that will live in infamy) and Tejas (NephOnDemand is a lot different today than it was in the early days), we were all pretty independent. I rarely interacted with them and they rarely interacted with me. I read their stuff and was influenced by what they were doing, but blogging was largely a solo affair. Now every post I write is either inspired by an interaction on Twitter; vetted, reviewed and proofed on Twitter; or has Twitter generated follow-up. The blog and the #NephTwitter community are inseparable.

At Kidney Week 2008 (the first after launching PBFluids) I live blogged some of the lecturers. Essentially I was live tweeting, but with Blogger. The results were not pretty (see this, and this, and this). I knew what I wanted to do, but Blogger was the wrong tool. I joined Twitter a month later.

exploring twitter

— Joel M. Topf, MD FACP (@kidney_boy) December 12, 2008

For the first two years on Twitter I barely used it. This was largely due to the lack of a community online. It wasn’t until 2011 that #NephTwitter started to become a thing. The blog was important, but Twitter allowed for the interactivity and collaboration that no other platform could provide. Twitter was the essential trigger for nephrology’s social media awakening.

Turning the microphone on.

In October of 2008, 5 months after starting PBFluids, Dr. Schwimmer linked to my blog. Getting a link from KidneyNotes turned the microphone on. It turned the blog from an ego project with an audience of one into a (very) limited publishing platform. Joshua made me a public physician.

monthly page views for the first year of PBFluids

The Smartphone Wars

PBFluids is older than the App store. So a lot of early posts looked at smart phones and how they were going changing medicine. At first it was iPhone vs Blackberry and soon after that, iPhone vs Android (I might have been premature when I called the results of this one).

In March of 2009 I had my first breakout post that received real traffic. It was a review of medical calculators for the iPhone. Don’t miss the follow-up post on MedCalc, which is still my go to medical calculator.

Best story of the blog

October 2010: ‘Meeting’ Margaret Atwood on Twitter.

The story was so cool it got picked up by the Guardian. If you ever wanted to know happens to traffic to your personal website when a post you wrote gets covered by The Guardian, take a gander:

The Madness begins

In March of 2012 I made this video for World Kidney Day.

I wanted to recreate the spirit of Shit Nephrologists Say for the following World Kidney Day. In February of 2013, Matt and I were brainstorming ideas and NephMadness was conceived.

NephMadness

My favorite line from that post:

I had my partners and fellows fill out brackets today. They all had a lot of fun doing it. There is something light and joyful pitting these heavy topics against each other in totally absurd ways. Take a crack at it, have fun.

Seeing Twitter nephrology get into NephMadness and care about it made me understand what was possible with FOAMed. It made me see that we could change medical education so it was woven into your online-life. We could make medical education feel less like the lonely library on a Friday night and more like a raucous but productive study group with your med school friends. It could connect nephrologists so that we could learn together, be smarter together, be stronger together, and have fun together.

The DreamRCT flash in the pan

In a fit of insanity I tried to shoe horn DreamRCT between the new year and NephMadness. Here was my entry in the first contest.

#DreamRCT: Prove the uric acid-CKD connection and win Richard Johnson a Nobel

The following year we moved it to the fall and partnered with MedPage Today. We had a great panel of judges and amazing entries. The reason there was not a year three of DreamRCT was not due to lack of great content. DreamRCT was a victim of trying to do this social media education in the cracks between clinic and rounds. Sometimes there are just not enough h=nights or weekend.

Here is my entry for DreamRCT 2: An EBM take on one of the fundamental problems with hyponatremia.

Please fund my #DreamRCT, it is just embarrassing how little evidence is found in hyponatremia

The second DreamRCT was also the capstone project of the first year of the NSMC. Four of the sixteen studies in DreamRCT 2 were written by our first four interns. Looking at the list of DreamRCTs it is amazing how many questions they brought up that are still taxing us. I particularly loved Scherly’s MIND study and Chi Chu’s RCT on contrast nephropathy.

NSMC

Speaking of the NSMC, it was also was launched on PBFluids:

The first Nephrology Social Media Internship

NephJC

Actually it was launched on NephJC.com, but NephJC.com itself was launched here:

#NephJC is coming

While writing this post I came across a lot of PBFluids deep cuts that I haven’t thought of for years. A few gems:

Area Codes, RTAs, and Amphetamine. This is what Twitter is like.

Another Twitter collaboration that turned into a fun post

There once a dialysis patient from Nantucket…

In the last year Twitter has really shake off many of the ancillary companies and services that grew-up around it to support the service. FavStar going away in a few weeks. Storify is gone. We have seen TweetChat and TChat.io lose so much functionality to be unusable. But the blog marches on. After a decade of change and innovation in the social media space there is still room for the blog. And more importantl,y the blog, with its dependence on simple HTML, the portability of its data, and its ability to reform itself (see my transition from Blogger to WordPress this year), has a durability that is valuable in Medical Education. I may not be publishing new content to PBFluids in 10 years, but the work that is here, will remain.

Happy Birthday PBFluids, it’s been a great ride.

May 23, 2018

Stop torturing the radial artery, VBGs are good enough.

I have been doing this for a few years, but now I am going to formalize it and add it to my lectures.

Really nice post at Taming the SRU.

May 16, 2018

Spooky Sodium, the Lecture

Last year’s NephJC on Jen Titze’s study on simulated Mars missions and sodium handling really baked my noodle.

Titze’s arm of research breaks the foundational laws of body fluids. Partly to help myself grasp the information, and partly to help spread this paradigm shifting research I created a 1 hour lecture on his work. I have given the lecture a few times, but I’m still not sure I have it right. I am offering the lecture to the internet to solicit comments. What did I get wrong? What is unclear? And I would like to add my outrage that when I went to the update in fluids and electrolytes pre-course that the ASN offered at Kidney Week this entire angle of sodium was completely ignored, except for one derogatory, snide comment. The legends of sodium, fiddling while their Rome burns .

One thing I am still having trouble with is the increased urine output at the highest sodium intakes. I get that free water clearance generates solute free water and this dilutes total body sodium decreasing the need to drink but this free water is only a hypothetical construct, it is not actually available to increase urine output. Right?

Here is the lecture: