Why we needed Kayexalate in the first place

In February I'm giving grand rounds on the Potassium Wars (what, you didn't realize we are in the opening stages of the potassium wars?). I was looking at the original research on Kayexalate from 1961 and came across this ad. Check out the doses of spironolactone they were slinging:

400 mg of spironolactone, daily and this is in a world without loop diuretics!

Purple Urine, now that's not something you see everyday

From the NEJM 2007.

Purple discoloration can occur in alkaline urine as a result of the degradation of indoxyl sulfate (indican), a metabolite of dietary tryptophan, into indigo (which is blue) and indirubin (which is red) by bacteria such as Providencia stuartii, Klebsiella pneumoniae, P. aeruginosa, Escherichia coli, and enterococcus species. The clinical course is benign, and the urine typically clears with resolution of the bacteriuria and acidification of the urine. 

H/T Life in the Fast Lane

The first Nephrology Social Media Internship

A few pioneers at the intersection of social media and nephrology have banded together to create an internship in social media. The founding members of the loosely coordinated Nephrology Social Media Collective (logo pending, but it should be pretty cool) are:

• Myself
• Swapnil Hiremath, co-founder and brain child of NephJC
• Matt Sparks, savior of Renal Fellow Network and co-creator of NephMadness
• Kenar Jhaveri, blogger at NephronPower and editor of AJKDblog
• Paul Phelan, contributor to NephJC, Renal Fellow Network and AJKDblog
• Jordan Weinstein, creator of UKidney
• Edgar Lerma, creator of #NephPearls hashtag and serial author

The idea behind the internship is to give guidance to doctors or students who want to become experts in social media. There are a number of different techniques and strategies in social media and we will provide the intern an opportunity to work with these techniques first hand. Projects that will be open to the interns include:

• NephMadness
• NephJC
• AJKDblog
• Renal Fellow Network
• Research
• UKidney
• DreamRCT

Technologies that the intern will be exposed to include:

• Podcasts
• Google hangouts
• Tweet chats
• Storify for curation
• Mail Chimp newsletters
• Twitter analytics
• Google analytics
• multiple blogging engines including:
• Blogger
• WordPress
• Medium
• SquareSpace

But more important than the technology, is that the interns will have access to our collective wisdom and have access to an instant personal learning network to allow them to pursue their personal social media goals. This is the first time we have done this and we are still working out the exact curricula, but if you are in nephrology, residency or medical school and want to learn how to leverage the power of social media consider applying for the position.

Link

Just another day at the PBFluids world headquarters

Waiting for me in my inbox today:

Hello Dr. Topf, 

My name is Julia XXXXX, and on behalf of Keryx Biopharmaceuticals, I’d like to introduce Keryx as a resource for you as you develop content for your blog, Precious Bodily Fluids, given your commitment to advancing understanding of renal diseases. I’d like to periodically share updates from the company to keep you informed regarding its lead therapeutic product and commitment to patients on dialysis.

In fact, Keryx just announced it has begun shipping AURYXIA™ (ferric citrate) tablets to wholesalers in the U.S. Auryxia is approved for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. Auryxia is the first and only absorbable-iron-based phosphate binder that is clinically proven to effectively control phosphate levels within the KDOQI guidelines range of 3.5 mg/dL to 5.5 mg/dL. The U.S. Food and Drug Administration approved Auryxia in September 2014. In addition, Keryx has created the “Keryx Patient Plus” program to assist with patient accessibility to Auryxia. 

For more information, please visit http://www.auryxia.com/. The full press release is below and includes additional information. 

If you are amendable, we will continue to reach out to share updates from Keryx and AURYXIA in the coming year that we hope will be useful for your readers and followers. 

Please feel free to reach out with any questions. 

Best, 

Julia

My reply

Julia,

Thanks for reaching out. I’m glad there is a new phosphate binder available for dialysis patients. I was wondering if you have any data that shows Auryxia reduces any patient oriented outcomes (e.g. hospitalization, mortality, fractures, morbidity)? And if not, is Karyx planning on doing such a study? And if not, why not?

Joel

Fingers crossed but with a skeptic's scowl

Topf gets taken to Dr. Zen's Design Woodshed

I try to design nice posters and one that I was particularly proud of was 2013's Assessment of the Nephrology Blogosphere that I presented at Kidney Week. 

PDF | Powerpoint

A few months ago I submitted it for a design critique at Dr. Zen's Better Posters. Well this tweet surfaced today:

I blog about a poster about blogging. #meta http://t.co/r7pg4Nxeiu See what works, what doesn't on this poster! pic.twitter.com/kyBYxRvK6A
— Zen Faulkes (@DoctorZen) December 18, 2014

The review isn't pretty:

The colours in the table are not explained anywhere. I am guessing “green”means statistically significant, and “orange” means... a decline in posts over time? Maybe that could be mentioned in the main text at the left. 

The table is big and dense. Again, I wonder if it could be simplified, either graphically (first step: remove the vertical gridline!) or even removed. If I’m reading it right, some of the information in the table is repeated in the graphs to the right of the table. 

The last line of the table - “Totals” - appears to be incorrect. It looks like most of those entries are means, not totals. 

Also, the text mentions 30 blogs, but only 22 are plotted.

I only plotted the 22 with the longest duration of publication. What was the point of graphing KidneyTalk's 6 posts over 2 months? (4 years after the last post, she still owns the URL) 

I also disagree with his critique of the QRcode and bit.ly link. I think QR codes mostly suck and for most people snapping a pic of a URL is quicker and more reliable. I also think every person should have a little home page for their poster where it can be downloaded and supplementary information made available. See the homepage to this year's NephMadness poster.

Overall this was great feedback and I swear my next poster will be better.

Over-indexing on medications

I have a patient with CKD stage four, diabetes and hypertension. In fact, I have a hundred patients with CKD stage four, diabetes and hypertension. However, this patient had uncontrolled blood pressures. Here is the nomogram from her home blood pressures:

She was taking once daily furosemide and we changed it to torsemide, for better pharmacokinetics. She returned a month later and her blood pressure was fixed, systolics equally distributed between the 120s and 130s. So a win for Torsemide, or maybe not...

She was excited because she had been reworking her diet and was no longer drinking pop. She was eating more home-cooked meals and really focusing on eating more vegetables and fruits. She was also being more conscious of her sodium intake.

When I walked into the room I was focused on the medication change, because that was my intervention. But the more I spoke with her, the more I began to lean to the lifestyle interventions. She was adopting spontaneous DASH diet:

• More fruits and vegetables
• Decreased processed and restaurant food
• Decreased fructose intake
• Improved compliance

She denied non-compliance on her previous visit, but her new focus on her health should certainly increase her medication compliance. All of this was in play. 

In the end, medicine is a giant, uncontrolled experiment and correlation does not equal causation. Just because you changed medicine doesn't mean that is was what fixed the blood pressure.

SIADH and lasix

I remember a time when I thought the treatment of chronic SIADH was going to be revolutionized by the vaptans. These small molecular ADH antagonists would interrupt the disease the precise mechanism of disease. I expected a Banting and Best like revolution. (If you have not seen the story of the discovery of insulin take a moment to watch the movie, Glory Enough for All, especially if you thought the greatest thing to come out of Canada was Tim Horton's)


The initial data was promising with convincing studies on conivaptan and tolvaptan, but something happened on the way to SIADH nirvana.

First the EVEREST trial went sideways. In heart failure:

• Angiotensin 2 is elevated and blocking it prolongs life
• The sympathetic nervous system is up-regulated and blocking it prolongs life
• Aldosterone is elevated and blocking it prolongs life
• ADH is elevated and blocking it doesn't do a damn thing

With no hope for a heart failure indication the drug was marketed solely as a treatment for hyponatremia where it was shown to be effective. The pitch was that doctors should not discharge people with hyponatremia and tolvaptan was faster and more effective than the previous standard of care. The drug was priced for short-term inpatient use at $300 a pill tolvaptan was a non-starter for chronic outpatient SIADH.

So generous of Otsuka to make the 30 mg dose the same price as the 15 mg

But I held out hope, I felt that as soon as the FDA licensed tolvaptan for ADPKD, the drug would be re-priced for chronic use and the price would come down. In fact during a TEMPO investigator meeting, an Otsuka executive hinted they would lower the price on approval (personal communication). However, despite being the only known treatment that slows the loss of renal function in autosomal dominant polycystic kidney disease, the FDA told Otsuka and the ADPKD community to pound sand.

Somewhere in there, Otsuka changed the labelling and limited tolvaptan to 30 days or less for hyponatremia, so the dream...is officially dead.

But my patients are still alive and they still have sodiums of 125. Demeclocycline, despite being a generic, is very expensive and not a good option. From the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association guidelines on hyponatremia:

The side effects reported for demeclocycline and lithium were such that we recommend not using them for any degree of hyponatraemia.

Fluid restriction, the cornerstone of therapy, is difficult to maintain and in severe cases is insufficient to correct hyponatremia (I'm thinking of patients with negative free water clearance). Urea has a good track record but I have not heard of it being used in the United States. Salt tablets can help, but often are inadequate to correct the hyponatremia.

On the list of possible treatments are loop diuretics. I have tried loops in hyponatremia on a number of occasions and though the math works, in my hands I have not found them to be effective. In the past, I have used loops in hospitalized patients with hyponatremia. The results have been underwhelming. But I know have a loop diuretic success story in a patient with significant but stable outpatient hyponatremia.

+1 “@medicalaxioms: Nothing aggravates a nephrologist like a kidney that refuses to obey the math.”
— Joel Topf (@kidney_boy) March 31, 2014

I met the patient when he was admitted to the ICU with mental status changes due to a sodium south of 120. This was not his first episode of hyponatremia. We corrected the sodium and restored normal mentation. We did a thorough work-up, looking for the etiology of the SIADH and despite some promising leads that turned into blind alleys, I am quite confident, now, that this is idiopathic SIADH.

During subsequent outpatient follow-up he had persistent hyponatremia with sodiums running in the high 120's. During this time, treatment consisted of salt tablets and fluid restriction. A couple of visits ago I added torsemide, and boom the two sodiums since have been 138 and 134.






Here is the sodium and urine osmolality over time. It plummets after the torsemide is started. This increases the free water clearance.

I also have data on the urine sodium, to get an idea of the electrolyte free water clearance. The change is not nearly as dramatic or convincing.

I have some of the data to calculate electrolyte free water clearance, but I'm missing urine volumes. We can determine the character of the urine from the following formula:

The following percentages represent the fraction of the urine volume which is electrolyte free water. The first three columns are negative, indicating that the urine the patient is producing has less than no free water. Urinating is more like drinking water as urination actually causes the sodium to fall, rather than rise. For a more in-depth explanation of the electrolyte free water calculation, check out this video.

It will be interesting to see if this improvement continues. I now believe that the reason I was underwhelmed when I used loop diuretics in the hospital is that I was working in the compressed time scale of inpatient medicine and only when you stretch the time horizon to months does the drug become effective. I think the reason it takes so long is that loop diuretics need to wash out the concentrated medullary interstitium, thus preventing the ADH from reabsorbing much water. A drug induced partial nephrogenic diabetes insipidus.

Yes, it's a little pocket of insanity but does it have something to teach us?

A few months ago there was a screen shot of a clinic note floating around the internet. It was, in the words of another nephrologist the most passive-aggressive nephrology consult note I have read in a long time:

Patient's sodium dropped further to 120 in the evening. He has had a precipitous drop that I suspect is due to over-diuresis, which does not seem to be a diagnosis within the lexicon of heart failure cardiologists. It is possible that he could have developed SIADH, through a drug side effect. In any case, we have reached the usual place where attempts to fix the heart have blithely interfered with renal physiology, and I am not willing to let his serum sodium decline into the 110s. If we give NS, and he has SIADH, we will worsen his serum sodium. We could use 3% NS, but he is not having mental status changes, yet, and this is bad form for a patient in heart failure. If he is volume depleted, and we use conivaptan, he could develop hypotension which would be difficult to fix. So I seem to have been finagled into ordering tolvaptan, which will hopefully prevent any further decrease tonight. Tolvaptan fixes a number and has not been shown to improve clinical outcomes with chronic use.

Clearly there is a large dose of crazy in the assessment and plan, but it highlights a number of real issues in hyponatremia. Let's dissect the note a bit and tease out the best parts.

The first clam that over-diuresis does not seem to be a diagnosis within the lexicon of heart failure cardiologists seems to be true. A brief survey of google finds a paucity of relevant hits for the phrase and most of those are from nephrologists or family practitioners. Given the frequency that I see patients suffering from this I was a bit shocked at these results.

The next sentence seems a bit preposterous, It is possible that she could have developed SIADH, through a drug side effect. Presuming that a patient with heart failure induced hyponatremia now has a second denovo disease seems a bit of a stretch, but we don't have access to the clinical data and so it is hard to determine if this is true. However the definition of SIADH requires that patients be euvolemic and judging from as much of the story as we know it seems like this patient is clinically hypervolemic. This rules out a clinical diagnosis of ADH, because the release of ADH in heart failure is due to physiological trigger for ADH, a decrease in perfusion. The disease of SIADH is specifically reserved for patients in which there is no physiologic stimuli for ADH release. The presence of heart failure and volume overload, definitionally rule out SIADH.

The next sentence is interesting: In any case, we have reached the usual place where attempts to fix the heart have blithely interfered with renal physiology, and I am not willing to let his serum sodium decline into the 110s. Diuretics increase water and sodium loss, but the cation content of the urine is almost always significantly lower than the plasma cation content, urinary sodium with loop diuretics is typically around 70 mmol/L. So use of loop diuretics cause loss of relatively more water than sodium and result in hypernatremia, except in heart failure. To understand why, one needs to understand electrolyte free water clearance (and an example of using it in the treatment in hypernaatremia is here). The higher the free water clearance, the less prone patients are to hyponatremia. Here are the calculations for electrolyte free water clearance for a patient with hyponatremia due to CHF before and after the addition of loop diuretics:

Before diuretics

In CHF, the patient is actually doing a pretty good job clearing free water. More than half of the urine output is electrolyte free water, the character of the urine is appropriate for correcting the hyponatremia. The problem is not the character of the urine but the amount. The patient just doesn't make enough urine to generate adequate electrolyte free water to account for the water the patient is drinking. Water restriction will be effective for these patients.

So, if the problem is an inadequate amount of urine the logical next step would be to increase the volume of urine with a diuretic:

With diuretics

Unfortunately, though the diuretic increases the volume of urine, it also changes the character of the urine. In this case, it dramatically increases the urine sodium content. This makes the urine almost completely ineffective at removing electrolyte free water and the net result is that the electrolyte free water clearances actually falls with the addition of the diuretic. This is the trap our poor nephrologist is raging against.

The next sentence of the rant: If we give NS, and he has SIADH, we will worsen his serum sodium. We could use 3% NS, but he is not having mental status changes, yet, and this is bad form for a patient in heart failure. I have a problem with this sentence and do not think it is well thought out. The nephrologists clearly believes this patient is over diuresed, we see this situations all the time and they respond briskly to additional fluids. Don't complain that the patient has been overdosed with diuretics and then refuse to provide the antidote for this overdose. I am skeptical of his theory that the patient has SIADH and it is a bit unreasonable to even give a trial of 0.9% saline. In regards to 3% saline, our good doctor might want to take a look at some of the data on the use of 3% saline in heart failure: SMAC-HF (PDF) or Seminars in Nephrology summary. While it is not standard of care the data are certainly intriguing and when the traditional approach is not helping the patient, as apparently is occurring in this patient, it may be worth a look.

The next sentence is regarding conivaptan: If he is volume depleted, and we use conivaptan, he could develop hypotension which would be difficult to fix. Conivaptan is a non-selective vasopressin antagonist, as opposed to tolvaptan which is a selective V2 receptor antagonist. Blocking V1 could cause hypotension as has been reported in multiple case reports. See this open access review.

So I seem to have been finagled into ordering tolvaptan, which will hopefully prevent any further decrease tonight. Tolvaptan fixes a number and has not been shown to improve clinical outcomes with chronic use. This complaint that tolvaptan fixes a number seems a bit obtuse for a nephrologists who was presumably consulted to fix a number. It also implies that tolvaptan is unique in that it has only been shown to fix a number. Well unfortunately, all the therapies of hyponatremia, outside of acute symptomatic hyponatremia have only been shown to fix a number. However given the profound morbidity associated with low sodium, it seems judicious to correct hyponatremia until data proves it is unhelpful. Additionally, to claim in one sentence that you refuse to allow the sodium to fall below 120 and in the next sentence to rail against a therapy that has only has been shown to fix a number seems to belie a profound lack of self awareness.

But keep fighting the good fight against the cardiologists, somebody needs to keep their egos in check. #PracticallySurgeons

Last chance to vote

The longest tradition in the nephrology blogosphere, the Renal Fellow Network's Nephrology Story of the Year! For five years RFN has been posting the top stories of the year and for the last few years they have been off loading the work to the crowd. So do your duty and vote.

Go vote. 

Polls close tomorrow. 

And to the losers stuffing the ballot box for "Perivascular Gli1+ progenitors contribute to myofibroblast pool leading to fibrosis in multiple organs including kidney Cell Stem Cell" I will not stand for that!

I'm pulling for Dendritic cell isoketals activate T cells and promote hypertension as covered in NephJC.

The newest nephrology blog: Nephrology Tweetbook

Run by master tweeter Nikhil Shah, Nephrology Fellow at the University of Alberta, Nephrology Tweetbook is primarily a collection of educational tweets with, as far as I can tell, a single long form post on the use of What's App as an educational tool. Very interesting use of the app.

I'm not sure what he is using to post the tweets to blogger, but he would get better, most useful posts if he used the embed code from twitter.

This is what his posts look like:

No active links.

If he were to use the embed tool in twitter it would look like this:

Nephrology Tweetbook: Text to Treat!! Yes yes yes! @ASNKidney http://t.co/OFVcLAq1TA
— Nikhil Shah (@dr_nikhilshah) December 8, 2014

Nephrology Tweetbook: NAGMA - Review. @kidney_md http://t.co/sLjWb9jPZU
— Nikhil Shah (@dr_nikhilshah) December 8, 2014

Nephrology Tweetbook: Say "PEE" photographing urine! @edgarvlermamd @nejm http://t.co/x8EkFogfjY
— Nikhil Shah (@dr_nikhilshah) December 8, 2014

It's a nice addition to the nephrology social media landscape.

Nephrology is rusting (Updated)

Another year, another horrible match.

Here is the press release: NRMP SMS Nephrology Match for Appointment Year 2015

Some of the highlights:

• 68 of 134 programs did not fill their positions
• There were 0.68 applicants for every fellowship position this is down from 1.5 applicants for every position in 2010

Onecurious aspects to the report: the authors wrote:

In AY2015, nearly every nephrology applicant matched, for a 95.2% Match rate.

But take a look at the table:

254 applicants and 254 positions filled, unless an applicant is doing double duty at a couple of programs, it looks like a 100% match rate.

The other fact that I'd like to know more about is there are 141 US medical schools, 6 of those are too new to have any graduates applying to nephrology, that leaves 135 producing 79 applicants. That means at least 56 did not produce a single nephrology applicant. And I bet at least a couple of schools send multiple grads to satisfying careers in nephrology.

What I want is a list of the schools who are failing nephrology and who is teaching nephrology at those locations. Let's put their heads on a stick.

On the other side of that coin is who is teaching at the schools that produce multiple nephrology applicants and what are they doing right. Lets give those teachers a medal.

Can we get the medical school data from NRMP?

@kidney_boy might be worthwhile looking at schools who train high # of students who want to be kidney docs, see what they do "right?"
— Heather Murray (@HeatherM211) December 4, 2014

A few thoughtful commentaries to balance out my tirade:

• Warren Kupin: A New Nephrologic Syndrome: Acute Fellowship Insufficiency
• Paul Phelan: Nephrology Workforce Crisis: Don’t Forget International Medical Graduates
• Kenar Jhavari: Nephrology at crossroads in 2014-2015

I'm doing grand rounds at the end of January and I'm going to get medieval on kayexalate

So I will be collecting resources on this page.



EMcrit Blog: Is Kayexalate Useless?
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