Lazy web: is Primo the only CKD-MBD trial without PTH as the primary outcome?

Primo was published a year ago in JAMA. I'm trying to think of another randomized controlled trial done in pre-dialysis patients looking at metabolic bone disease. I think PRIMO is the only one that looks at an end-point besides PTH. Could that be right?

I must be forgetting one (or a dozen)...

Ooops. Forgot about the proteinuria trials:

Extreme Hypernatremia

Yesterday's post has stimulated a lot of interesting discussion on Twitter. I have updated the post with some of the tweets. Here are two more that have stimulated some additional thoughts:

@kidney_boy In a case like this would dialysis be better? Or if youre just going to give him free water back, what about a loop diuretic too?
— Matthew Wong (@MatthewLWong) June 11, 2013

@kidney_boy @skepticscalpel This and water poker poisoning incident. Posters for "the dose makes the poison."
— Casey Lyons (@lyonscas) June 10, 2013

When I was discussing the case with my dad, a surgeon, he kept asking if I would have given a diuretic. I wouldn't. In fact I wouldn't have managed the case like the doctors in the case report did.

Now before I express my criticism, it must be noted that the doctors took on a lethal poisoning and undoubtedly saved his life. Criticizing their management may appear to be deducting style points from a walk off home run, who cares if they swung at a bad pitch, they won the game. I want to recognize the bravery, intelligence and success of the medical team but I don't think it was ideal care and I feel they were just as lucky as they were good.

The crux of their treatment was a massive infusion of D5W. Dextrose infusions are the bedrock of treatment of hypernatremia. The reason is that most routine cases of hypernatremia are due to water deficits:

• diabetes insipidis
• dehydration
• altered mental status
• disrupted thirst mechanics. 

Outside of treating the side effects of too much sodium bicarbonate (remember the sodium concentration in an amp of sodium bicarbonate is 1,000 mmol/L) we don't routinely see hypernatremia from salt overdoses.

This patient did not suffer a water deficit, he had salt overdose, a month worth of sodium in a single quart. I think the infusion of 6 liters of D5W in 30 minutes had a high chance of causing serious problems, especially since the patient in question was not volume or water depleted. Not only was he not volume depleted, the high serum sodium was pulling water from the intracellular compartment and shifting it to the interstitial and vascular space,  so not only was he not volume depleted, he likely was volume expanded. The treating doctors took a patient with a lethal sodium ingestion and treated it with a lethal water ingestion (Jennifer Strange who died in the tragic Wee for a Wii incident ingested 7.5 liters over 2 hours).

While in most cases of hypernatremia we give water because that is what is missing, in this case we need to remove the sodium. The treating doctors decided to depend on the kidneys to clear the excess sodium. The kidneys did an admirable job with extremely high urine sodium levels and concentrated urine, however they made that decision while his creatinine was going up. That seems a bit questionable.

The fluid also raised his glucose and lowered his potassium (the D5W infusion dropped the potassium from 5.1 to 2.5 in 30 minutes, I suspect this was an insulin effect). The increased glucose actually blunted the decrease in osmolality that occurred during treatment. In fact if you calculate the osmolality, the infusion of D5W had a surprisingly modest effect on serum osmolality, especially compared to it's effect on the sodium concentration.

If you do any math on your Mac you stop using the calculator and buy Soulver.

Large change in sodium with 6 liter D5W infusion

Much more modest change in osmolality due to D5W induced hyperglycemia

Again, the treatment worked and perhaps the hyperglycemia helped protect the brain or ameliorated the cerebral desiccation of hypernatremia. I don't know.

Some may argue that since glucose is not an effective osmole we should not be concerned about it. I think it was an effective osmole do to the lack of insulin activity (evidenced by the high serum glucose). Just like we see cerebral edema from the rapid reduction of glucose in kids being treated for DKA, that is a situation where changes in a normally ineffective osmole cause movement of water.

My dad wanted to use a diuretic because he wanted to get rid of the ingested sodium as fast as possible. The problem with a diuretic is it will decrease the maximum urine concentration so that sodium excretion occurs at a lower urine osmolality increasing urinary water losses, exactly what you don't want in this situation. The patient was making a large amount of urine and eventually got his urine sodium up to 270 mmol/L and urine osmolality up to nearly 1,000 mOsm/Kg H2O. If he was given furosemide he would not have been able to achieve that degree of efficiency.

I would have been nervous about trying to administer 6 liters of fluid in 30 minutes and assuming dialysis could be arranged to run without delay (impossible in the middle of the night and difficult to assure during the day) I would have selected that option. The reason I like dialysis is that it would remove the toxin, sodium. 

Something that most non-nephrologists don't recognize about dialysis is that though hemodialysis removes sodium it does not remove it by diffusion, the process by which it removes every other toxin. The dialysate has a sodium concentration that runs from 140 to 150 mmol/L, essentially isotonic. No concentration gradient means no clearance from diffusion. Sodium is removed by ultrafiltration. That means when we remove 4 liters of fluid with dialysis (we essentially use the pumps to squeeze 4 liters of plasma through the membrane's pores, and those four liters contain isotonic sodium, so 4 liters x 140 mmol/L = 560 mmol of  sodium removed from the body.

In this situation there would some removal of sodium by diffusion because of the extreme hypernatremia and there would be additional removal by ultrafiltration, depending on how much fluid I removed. I would start a D5W infusion at a liter an hour and remove 4 liters of fluid over a four hour treatment. I would check plasma sodium and osmolality every hour and, and, I don't know how fast I would go:

1. Should I try to normalize the sodium as fast as possible? 
2. Should I lower the sodium as fast as possible until the seizing stops and spontaneous movement returns?
3. Should I lower the sodium at a target rate of 12 mmol/L per hour? 5 mmol/L per hour? 2 mmol/L per hour?

I don't know but if forced to make a decision I think I would go with answer 2.

How would you manage a sodium of 191?

Saltiest Sodium. Dumbest Dude.

My work-shop on sodium includes a bit on all the cases of hyponatremia due to fraternity hazing.

• Mathew Carrington
• Walter Dean Jennings
• Braylon Curry

I also include the crazy case of Jennifer Strange.

But I had never heard of idiot induced hypernatremia until this case report:

A nineteen year old male drank a quart sized bottle of soy sauce on a bet.

Two hours later he was brought to the ER comatose and seizing. His sodium was 177. They initiated hypotonic fluids and arranged transfer to a tertiary care center. At the tertiary care center the sodium was still higher at 191. The doctors then changed the fluids to D5W at 12,000 mL per hour. They gave 6 liters of D5W in 30 minutes.

After the infusion he opened his eyes and regained spontaneous movement. He was discharged on hospital day four neurologically intact with only some minor abnormalities on the head MRI, all attributed to postictal changes.

How high is a sodium of 191? MedCalc will not even accept it as a possible sodium concentration:

A couple items of note:

• The infusion of D5W raised his serum glucose from 365 (hyperglycemia causes insulin resistance) to 1,116 mg/dL.
• The authors do not comment on what access they used to infuse D5W at a liter every five minutes.
• In addition to the hyperglycemia, the D5W infusion dropped the potassium from 5.1 to 2.5 in 30 minutes! That is kind of terrifying.
• The authors use the Katz correction for hyperglycemia, (eat it Hillier).
• The authors do not discuss how they decided on 6 liters of D5W. Full correction down to 140 would by roughly 12 liters, so perhaps they decided on 12 liters in an hour with continuous neurologic assessment and when he began to have spontaneous motor movement after 30 minutes they slowed down.

Some nerdery about the sodium exposure: He drank a quart of soy sauce. A quart is 946 mL. The article states that soy sauce is 17-18% sodium chloride. Here are some meta calculations, in case you are interested:

Read the article, it's a good read and it has the highest urinary sodium I have ever seen, 270 mmol/L (almost twice as salty as normal saline). They discuss other extreme hypernatremic conditions, and theories on rapid or sow correction.

Hat Tip Skeptical Scalpel

Slides for Keynote | PDF

Update from Twitter:

@kidney_boy I would guess they used a pressure bag or infuser (e.g. Trauma 1) to get in a L every 5 min
— Seth Trueger (@MDaware) June 10, 2013

@mdaware @kidney_boyA good 14 ga 1.75 inch peripheral IV can do 333 cc/min with a 1 meter pressure head to gravity.
— philroman (@philroman) June 11, 2013

@kidney_boy I've seen 216 before. Started at 196, rose more with initial NS administration. Kid with ichthyosis, and bad dehydration.
— Ken Tegtmeyer (@pccm_doc) June 11, 2013

July first approacheth

I wrote a post for the Pediatric Career blog. It is about July first, the most significant date in the academic medicine calendar. I did not discuss patient risk or medical mistakes. I have blogged about those before. I discussed how to leverage this new beginning to develop a fulfilling and productive career in medicine. Read it.

Medicine, 4 log units above normal!

Highest CPK I have ever seen:

That is the first CPK over one million I have seen. I love how the CPK of 4,000 on day one, you know the CPK that os 20x the upper limit of normal, is not high enough to even be rendered on the graph. For the scientific-minded here is the same data on a log rhythmic scale:

We were able to successfully alkalinize the urine (EBM purists can bite me, I  believe the bench data here) and she never became oliguric, however on day three her potassium was 7 and we initiated dialysis. Surprisingly, phosphorous never got out of control.

She also had the highest CRP I have ever seen, 147.

The etiology you ask? She presented three days after a sore throat. We initially discounted viral rhabdo because the CPKs were so high but the Coxsackie B type 3 and 4 antibodies were off the scale and the literature is sprinkled with similar case reports (here and here). Muscle biopsy results are pending.

Muddy brown cast (day one, unspun specimen):

Urine sample (day two with urine pH of 8.5), no red cell on U/A

Still can't believe I didn't get a picture of the urine on the first day, it was black.

.@kidney_boy re:CPK I see Phos was never uncontrolled - anything to say about Ca both at presentation & during alkalinisation? #nephrology
— Tom Oates (@toates_19) June 4, 2013

See this:

Best post I have read on how to pay donors for kidneys

If you want to start a fight among nephrologists, start talking about paying donors for their kidneys. This may be the most contentious issue in nephrology. I personally am a believer in the concept but trying to imagine a free market for organs makes me nauseous.

Rohin Dhar, at the Priceonomics Blog has put together a brilliant, straight-forward essay describing the problem, showing how current ideas for increasing the organ supply (make donating organs the default after death, paired kidney donation, improved donor-recipient matching) are not working and cannot hope to solve the problem and then goes on to describe a hypothetical organ purchasing system run by medicare. I'm convinced.

When discussing this on twitter, the always interesting Christos Argyropoulos talked a bit about the problem with Greece's implementation of default organ donation:

@kidney_boy The Iranian system was covered last year in KI if I am not mistaken. Opt out can also backfire as it has in Greece
— ChristosArgyropoulos (@ChristosArgyrop) May 29, 2013

@kidney_boy Opt out legislated in 2011;hugely unpopular, a couple of high profile resignations from the Ntl Transplant body-> # of Txps down
— ChristosArgyropoulos (@ChristosArgyrop) May 29, 2013

@kidney_boy Public pushback makes ICUs reluctant to refer donors,even though almost everyone is. Opt out systems are embraced not imposed
— ChristosArgyropoulos (@ChristosArgyrop) May 29, 2013

An open access review of Iran's transplant system can be found here (A non-systemic review from McGuil University? I grow feint.) Here is the Kidney International paper Dr. Argyropoulos was referring to.

Look at how the number of transplantations is growing in Iran:

Mitra Mahdavi-Mazdeh. Kidney International, 2012

While it is flat in the US:

USRDS

The current system of paired exchanges and campaigns for kidney donors has noble intentions, but it’s not working. People are needlessly dying as a result.

--Rohin Dhar

And therefore never send to know for whom the bell tolls; It tolls for the TTKG

I was never a big fan of the trans-tubular potassium gradient. I taught it because it was expected core knowledge for medicine residents. While I thought it was a poor test to assist in clinical management I delighted in using it to teach physiology. Understanding how the TTKG works, why it works and the thinking behind the exclusion criteria required sophisticated understanding of potassium and solute handling in the distal nephron.

My primary complaint of the TTKG was how useless it was in the assessment of hyperkalemia. In persistent hyperkalemia the TTKG is always inappropriately low (except in cases of rhabdomyolysis or tumor lysis syndrome where it is possible to get persistent hyperkalemia despite normal renal potassium handling, woe to the patient, whose doctor is relying on the TTKG to diagnose rhabdo). The TTKG was not useful for differentiating the various elements of renal potassium handling that can go off the rails to cause hyperkalemia.

The TTKG could do a neat job of differentiating renal from extra-renal potassium losses in hypokalemia.

Then in 2011 this article came out which showed urea cycling to occur in the late cortical collecting duct. The authors believed that urea delivery to the cortical collecting duct was an important driver of potassium secretion. This broke one of the central assumptions of the TTKG: that no appreciable solute resorption occurs in the medullary collecting duct, the only reason the osmolality increases is the absorption of water.

It looks like the editors of UpToDate have voted the TTKG off the island, here is what UpToDate has to say about the TTKG. In Evaluation of the patient with hypokalemia:

Trans-tubular potassium concentration gradient — The transtubular potassium concentration gradient (TTKG) has been primarily used in the evaluation of patients with hyperkalemia. However, we do not recommend using the TTKG. Details pertaining to the TTKG and the reasons for our recommendation not to use it in hyperkalemia are discussed in detail elsewhere. (See "Causes and evaluation of hyperkalemia in adults", section on 'Transtubular potassium gradient'.)

In Causes and evaluation of hyperkalemia in adults

Trans-tubular potassium gradient — It would be desirable to assess the degree of aldosterone activity in patients with hyperkalemia by estimating the tubular fluid potassium concentration at the most distal site of potassium secretion in the cortical collecting tubule. Although this measurement cannot be made in humans, it was proposed that the potassium concentration at this site could be estimated clinically from calculation of the transtubular potassium gradient (TTKG) [91-93]. 

However, in a later publication, the authors of the original studies found that the assumptions underlying the TTKG were not valid [94]. It was concluded that the TTKG was not a reliable test for the diagnosis of hyperkalemia. We recommend not using the TTKG to evaluate patients with hyperkalemia.

RIP TTKG

Hey Hey it's your birthday!

Five years.
584 posts.
545,000 pageviews.

Monthly page views. (The posts from 2007 are back dated pages written at a later time that I use for my schedule
and some other projects, first true post was May 30, 2008. Work arounds for dealing with the limits of Blogger)

The first peak is my review of medical calculators for the iPhone.
The second peak is the Margaret Atwood Super Hero Costume experience.
The most recent surge looks less like a peak and hopefully a new plateau, I don't know the reason but it may have something to do with Google rolling out Penguin 2.0. Decreased search results for spam presumably mean more research results from high quality content.

I asked for a list of nephrology blogs last week and I know have what I believe is a comprehensive list of nephrology blogs oriented to medical professionals. There are dozens (hundreds?) of patient blogs and I did not include those unless they included significant scientific and or nephro-medico-politico content (see Hemo-Doc and Dialysis from the sharp end of the needle). I have found 30 blogs:

Looking at the data you can see how ordinary PBFluids is. The average number of posts is weirdly average, there are a number of blogs with more posts (I fully expect to be passed by the Kidney Doctor in his next bolus of productivity). It is only remarkable in that it is the third oldest active blog, behind the Renal Tsar and RFN.

I also asked you to vote for your favorite post (here and here). We have a winner:

• Dialyzing the highest potassium. If you are interested in that post I would recommend also looking at all of the posts tagged potassium.

Other honorable mentions:

• When 1A Evidence is not 1A Evidence
• Do we need to evolve our views on EBM in dialysis?
• Cool Wikipedia page of the day: Hickam's Dictum.

The blog has been a total gas and I really appreciate all the readers and their feedback. Five years down and I still have plenty of steam. I look forward to celebrating the blog bar mitzvah in 2021.

Tomorrow PBFluids turns Five

Please take a moment to vote for your favorite post on PBFluids.

App.GoSoapBox.com. Three times a charm.

I have been trying to use GoSoapBox to add some interactivity to my lectures. My first attempt did not work out at all like I wanted it. I used quizzes instead of polls. Then I added  GoSoapBox elements to my non-anion gap lecture and I tried to use it at McClaren Macomb a couple of weeks ago. McClaren built this beautiful auditorium under the hospital. It is state-of-the-art in every way except it has no way to plug in your laptop. My Kingdom for a free VGA cable. So I had to run the lecture off Dropbox on the Window's machine they had available. Not surprisingly it looked like ass. Then, when I tried to use GoSoapBox, I found that the auditorium had no cell signal penetration (basement) and no wifi (whiskey-tango-foxtrot). Who builds a modern auditorium like that? Total Fail.

On Tuesday I gave the same lecture to the Internal Medicine Residents at Providence. This time the system worked great.

Non-anion gap metabolic acidosis (Powerpoint, PDF)

As the residents were getting food I was joking with a few them and we were stuck on what Batman's father's name was. The residents found the Social Q&A section and used it to provide the answer.

I started the lecture with a couple of slides walking them through logging in and getting familiar with the system.

Then I had them do a pre-test to assess what their baseline knowledge of the subject was

Then I posted an ABG and asked them to interpret it.

Use of Winter's Formula

I had a series of questions on the proper use of the urinary anion gap.

And the lecture finished with a series of quick case vignettes designed to test knowledge of NAGMA.

The feedback on the system I received from the residents was excellent. They loved it. I made a mistake of using my laptop to both run the presentation and manage GoSoapBox. GoSoapBox requires the presenter to open the polls at the appropriate time so students can't see the poll until the appropriate time. Powerpoint got cranky when I would bounce to my web bowser and then back. Next time I will manage GoSoapBox on my iPad.

Disclaimer: I was given a free 6 month trial of this product. I have received no additional payment or inducement for promotion. I was looking for a system like this and Gary Abud, a friend and Michigan Teacher of the Year, suggested I give this a try. He arranged the free trial.

The Road to NephMadness

I know I said I would stop talking about NephMadness, but I just got a headset in order to record screen casts and I wanted to try this out. This is my first Screencast, as delivered at Beaumont's MedEd Week.

Road to #NephMadness from joel topf on Vimeo.

If you ever wanted to know what the traffic at PBFluids looks like?

Ever wonder how many copies of the Fluids book are out there?

Ever wonder what the hell the Microbiology Companion is?

All of these secrets and more are revealed in the presentation.

Medical School as a Tumblr

Here are posts tagged kidney.