Saturday, December 27, 2014

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!

Tuesday, December 23, 2014

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.

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 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. 
My reply

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?

Fingers crossed but with a skeptic's scowl

Thursday, December 18, 2014

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:

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 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.

Wednesday, December 17, 2014

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.

Saturday, December 13, 2014

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 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.

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.

Friday, December 12, 2014

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

Thursday, December 11, 2014

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.

Monday, December 8, 2014

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:

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

Thursday, December 4, 2014

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?

Sunday, November 23, 2014

Social media session at ASN Kidney Week

At the 2014 Kidney Week the ASN hosted the first session on social media. The session was moderated by Mathew Sparks and Kenar Jhaveri.

The session had four speakers:

  1. Bryan S. Vartabedian, MD. led off the session with his talk, The Public Physician: The Emerging Role of the Physician in a Connected, Always-On World. 
  2. Margaret S. Chisolm, MD. followed with her talk on Social Media Challenges to Professionalism: Do the Rules Change or Do We Change Social Media?
  3. The next speaker was a rarity at Kidney Week, a patient. Sarah E. Kucharski gave a highly personal story: Patients Turning Likes and Retweets into Healing: Social Media and the Age of the Empowered ePatient.
  4. I anchored the session with a talk titled, Social Media: How to Get Started, which would have more properly titled, Twitter for Nephrons.
A recreation of my talk is below, and you can also download the Keynote slides here.

Dr. Chisolm's persentation is here:

Kidney Talk - Created with Haiku Deck, presentation software that inspires

Matt did a great job of summarizing the Session for AJKDblog.

If you want to see the tweets during the two hour session and the hour afterwards, here is a transcript, (and part 2)with 534 tweets during the session and the one hour after. It is contaminated with other KidneyWk tweets so you have to filter through the list but there are some gems.

Here is a filtered and curated transcript:

Wednesday, November 12, 2014

Play Kidney Week Bingo

Record all of your misadventures at kidney week with Kidney Week Bingo.

Publicize your exploits as you go, by tweeting them with the hashtag #KidneyWkBingo

There will be a prize for the first person to get claim Bingo.

Thursday, November 6, 2014

Kidney Week Approaches

Next week the nephrology world will gather in Philadelphia for the annual ASN Kidney Week. This will be the most social Kidney Week ever. If you are interested in social media and nephrology I'd like to call your attention to a handful of events:

Thursday November 13 ASN Special Session on Social Media. 10:30 in Room 201C. This is the first time social media has been covered a part of the core curriculum at ASN. It should be awesome. ASN has assembled an all-star team to present:
Thursday at 12:45 CJASN and the guys from eJC will be running a session on doing A Better Journal Club. I think I will be speaking for 5 or 10 minutes about my experience with NephJC. Room 104 of the Pennsylvania Convention Center.

Thursday night at 8:30 pm, Blogger Night (after the ASN Presidents Reception). If you like the Neph Social Media Crew from Twitter, Renal Fellow Network, AJKDblog or NephJC, join us for drinks at Field House Philly. It is a sports bar. Look for me in the AJKD hat.

Saturday 10-12 Poster Session. SA-PO661 NephMadness Poster session. Sucks that I'll have to miss late breaking trials, what is usually the best session of the week, but oh well. I'll have to keep up via Twitter.

Saturday 12:30-1:20. NephJC Live. NephJC is doing a live ancillary session. We will take the awesome dynamic of the twice monthly twitter chats and see how well it translates to a live session. We have two young investigators presenting data.

The first is Deirdre Sawinski, MD, Assistant Professor from University of Pennsylvania who is going to speaking on her study of kidney transplants in HIV positive patients.

The second is Francis Wilson, MD who will be presenting data from a recently completed RCT on acute kidney injury. In addition to a platinum pated CV he is an experienced singing waiter so hopefully we will get an ad hoc performance.

NephJC Live will also be awarding the first Nephrology Social Media Awards. We will be giving awards for best tweeter, best new tweeter, best blog post about the conference and best curtain of the conference (best Storify related to ASN Kidney Week) I will have a post on the Social Media Awards later this week-end.

The thing about the NephJC Live is that if you want to come you need to register by Sunday, November 9 so we can buy you lunch. Registration closes on Sunday. Register now.

Thursday, October 9, 2014

Ever heard of Chinese Restaurant Syndrome? Updated

From a letter in the 1968 NEJM:

In a world full of weird coincidences, just days after that tweet, Ira Flatow from Science Friday fame covered Chinese Food Syndrome:

Friday, October 3, 2014

Questioning Medicine, sweet podcast.

This morning I received this tweet:
Somehow it reminded me of an email I once received from Nigeria:
So I hid my checkbook before I went and checked out the podcast. No worries, they never asked me to send any money to complete the download or authorize my listening. It was just a great medical podcast. The two hosts have excellent chemistry and the discussion was astute and evidence based. I highly recommend it.

You can find Questioning Medicine in iTunes.

Wednesday, October 1, 2014

Kidney Transplant Report Cards are Out

The Information from the Scientific Registry of Transplant Recipients (SRTR) publish transplant statistics for every transplant center. 7/2/12 – 6/30/13

Here are the results from Michigan. St John's is doing a great job!

Monday, September 22, 2014

Pentoxifylline in renal disease, a tour through the literature

Tomorrow is another exciting edition of #NephJC. We will be discussing pentoxifylline in diabetic nephropathy. There is a summary of the article at

In support of that article and to aid the discussion, Christos Argyropoulos has stepped up to the blogger plate to provide some color on pentoxifylline.



In wild anticipation of next week’s #NephJC on Pentoxifylline (PTX)  let’s go over some of the known facts about the drug:
  • It is a non-selective phosphodiesterase inhibitor.  PDEs are enzymes that inactivate cyclic nucleotides and have been organized in 11 families (Table 1 [1]) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1) [1] increases cAMP & stimulates PKA activity. 
  • Activation of PKA leads to phosphorylation of the cAMP response element binding protein (CREB) which in turn leads to suppression of the TNF-a[2,3] synthesis at the transcriptional level
  • Inhibition of cAMP production by these phosphodiesterases has a broad range of immunomodulatory effects (Table 2[1])
  • The drug also affects red cell deformability and favorably affects microcirculatory blood flow
  • “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis
  • Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres)
  • Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)

Sunday, September 21, 2014

Is this the best review on treating hypertension in pregnancy? Updated

Note: this is a living post that is growing as I brush up on preeclampsia

From Hypertension:

Update on the Use of Antihypertensive Drugs in Pregnancy


Another great article:

New aspects of pre-eclampsia: lessons for the nephrologist

Also with a free PDF. Thanks NDT.

Although these renal changes in general are believed to resolve completely after delivery, recent evidence suggests that pre-eclampsia may leave a permanent renal damage.
CKD is a risk factor for pre-eclampsia in advanced CKD 3-5, weak evidence
the risk for pre-eclampsia and other pregnancy complications is sub-stantially increased in women with chronic kidney disease (CKD) stages 3–5 
 CKD 1-3 is not a risk factor unless the woman also has hypertension, higher quality evidence.
but these women were not at increased risk for pre-eclampsia. However, there was a significant biological interaction between eGFR and hypertension making eGFR 60–89 ml/min per 1.73 m2 a risk factor for pre-eclampsia if the women were also hypertensive.
Pre-eclampsia increases the risk for subsequent kidney biopsy and subsequent ESRD:
In the first study, women with pre-eclampsia in their first pregnancy had a considerably increased risk of developing kidney disease that needed investigation with a kidney biopsy [Adverse Perinatal Outcome and Later Kidney Biopsy in the Mother in JASN]. 
women who previously had pre-eclampsia had a four to five times increased risk of later end-stage renal disease, independent of primary renal disease [Preeclampsia and the Risk of End-Stage Renal Disease in NEJM]. Women with recurrent pre-eclamptic preg- nancies and women who gave birth to offspring with low birth weight had an even higher risk. The increased risk remained significant throughout the follow-up period of nearly 40 years. 

 In regards to the natural history of pre-eclampsia:
It should also be kept in mind that although the extensive glomerular changes during pre-eclampsia are believed to completely resolve after pregnancy [The Glomerular Injury of Preeclampsia in JASN], no studies have routinely performed a kidney biopsy months after the pre-eclamptic pregnancy. The fact that as many as 20–40% have microalbuminuria after a pre-eclamptic pregnancy may argue for a permanent glomerular damage in a great proportion of these women [Microalbuminuria after pregnancy complicated by pre-eclampsia in NDT, Blood pressure and renal function seven years after pregnancy complicated by hypertension].
Warning about these conclusions regarding pre-eclampsia causing CKD:
When interpreting the studies of pre-eclampsia and later kidney disease, it should be remembered that pre-eclampsia might unmask asymptomatic or undiagnosed CKD, a disease that might have been present also before pregnancy. A pre-pregnancy eGFR >60 ml/min per 1.73 m2 measured at screening was in a population-based sample associated with future pre-eclampsia risk in hypertensive women [Kidney function and future risk for adverse pregnancy outcomes in NDT]

This article by Eiland, Nzerue, and Faulkner in PubMed Central does a nice job reviewing the pathogenesis of the preeclampsia.

Friday, September 19, 2014

ACEi talk.

A pharmacist from Blue Cross, Kim Moon, sent me an e-mail and told me she was a fan of the PBFluids and my and twitter. That, of course, instantly made her my newest bestie. She then asked me to do a webinar addressing common issues that prevent primary care doctors from prescribing ACEi/ARB to patients with diabetes. I agreed, anything for a fan of the blog.

A couple of months ago and long before the lecture was written she needed a title, so I threw out, "ACE inhibitors, the good, the bad, and the ugly"

Then I saw this tweet:
How embarrassing. Well, here's the show:

Link to video (740MB)
PDF (52.4MB) 
Keynote (132MB)

Streaming the video from google drive seems to be broken. Here is a forum describing the problem, and Google's lack of response to the issue. My work around has been to pony up the $60 and join Vimeo plus.

Thursday, September 18, 2014

Imagine if the wards were really like the boards

1. You have a new patient with a drug you've never heard of before. Your next step is to:

  1. Look it up on your phone.
  2. Ask a colleague what the drug is.
  3. Take a careful look at the patients medical history and try to figure out the purpose of the drug from the context. Hopefully it won't be relevant to the question you are asked.

2. The patient develops an infection and ID suggests adding clarithromycin. The patient is on a number of cardiac drugs and you are worried about QT prolongation. You should:

  1. Look up the possible interactions on your phone.
  2. Depend on your memory of potential drug-drug interactions. Because, though you hate to brag, you did pretty good in medical school and have a keen mind.
  3. Give the clarithromycin, but also order telemetry for the patient, because you are a careful doctor.

3. A patient presents for confusion and is found to have hyponatremia. She has the following labs:

  • Urine Na 80
  • Urine K 40
  • Serum Na 105
  • Urine output 600 mL over the last 18 hours
Calculate the electrolyte free water clearance.
  1. Don't worry that you are bad at math, this is probably SIADH so just prescribe tolvaptan.
  2. I can't remember the equation, but this just smells like an experimental question. I'm sure I can take care of the patient without this calculation. Let's look at the possible choices and I'll take a logical guess.
  3. Fire up MedCalc, put in the values. Out comes the answer.

4. The biopsy comes back for a patient with proteinruia. The Pathologist calls it dense deposit disease. You have never seen a patient with this before but you did do presentation on MPGN type two 11 years ago in fellowship.

  1. Perfect, you've got this. This is nephrology, there's no way the standard of care has changed in the last decade.
  2. Hit the computer and look it up on UpToDate and do a quick lit search focusing on the top nephrology journals. Consider eculizumab.
  3. Review KDIGO GN clinical practice guidelines. Scream out loud when you find that it is not covered. Fall back on answer 2.

Tuesday, September 16, 2014

New neph blog: UC Kidney Stone Program

Fred Coe and the crew from University of Chicago have started a kidney stone blog. This is the most prominent nephrology scientist to stick his toe in the blogging world. Dr. Coe was one of my teachers when I was at the University of Chicago (I blogged about him here and here). Dr. Coe has been instrumental in establishing the foundations of kidney stone science and continues to move field forward. He was a category in 2014's NephMadness:
(5) Dr. Charlie Pak versus (4) Dr. Fred Coe 
Charlie Pak and Fred Coe are the Bob Knight and Dean Smith of kidney stones. Not only did they dominate the field and do the pioneering work establishing the fundamental discoveries of the field, but they also trained the next generation of stone scientists that are currently leading the field. 
To this day the centers where Pak and Coe worked are world leaders in the field. In a plot twist, that would most likely happen in a comic book origin story, they were classmates at the University of Chicago Medical School, class of ‘61, and then were residents together at U of C. 
Dr. Coe remained at University of Chicago but Pak went elsewhere to established the Clinical Research Center and a new Division in Mineral Metabolism at University of Texas Southwestern Medical Center at Dallas. 
They even jointly won the Belding Scribner Award from the ASN in 2000.  
Intellectually they have staked out differing areas of excellence, Dr. Coe has focused on the the importance of the earliest stones to be anchored to the kidney. The location for these tiny early stones is Randall’s Plaques. The theory is that these tiny crystals form in the interstitium adjacent to the thin limb of the loop of Henle, they grow and eventually erode into the renal papilla. There, they are in contact with  supersaturated urine which can deposit calcium oxalate (or other other types of stones?). The plaques can be seen on cystoscopy and their presence predicts stone formers. Stone formation correlates with the degree of plaque coverage.
The blog is full of scientific and practical advice about kidney stones. His first post about why a blog is particularly insightful. 
A blog post is not a book chapter, a review article, a scientific article, or even a newsletter but something else entirely. It is the exact right size to convey one point and no more. It has no room for ornament or circumlocution, for fuzziness or indirection or even for two different points. You cannot avoid that moment when the main point must ring out clearly.
And this paragraph is just so Coe:
Being a singular, real, and immediate focus of attention, a point is something to work with. We can debate it, dissect it, even dismiss it if evidence permits or its logic is flawed. If a point appears to be sound, people can accept it as true for the moment, as an element that can be put together with like elements to make a picture of reality for this one disease. It is a picture that is true for the moment, arising as it does from science, just as the moment caught up in the pointillist net of Georges Seurat’s exquisite Sunday Afternoon on the Island of La Grande Jatte, being great art, will be true forever.

Welcome to the blogosphere Dr. Coe, we look forward to your posts. Your blog has earned a spot on my list of Notable Nephrology and Medical Blogs.

Sunday, September 14, 2014

Lecture on modern strategies to keep up to date in the medical literature. #FOAMed at Work.

I love it when fellows turn the tables on their attendings and school them on how the kids do it today.

Kamran Boka is currently a critical care fellow at Henry Ford Hospital but when he was a wee resident he worked with me at St John Hospital. This is an excellent lecture, make sure you check it out. Boka is fully engaged in the 21st century medical infosphere:

Check it out. He has important lessons for everyone.

Thursday, September 4, 2014

Urine specific gravity, not that great at estimating osmolality

I have a clinic patient with SIDAH and until the FDA regains some sanity and Otsuka provides a more rational price this will continue to be a frustrating battle. This patient had some pretty typical labs for a patient with SIADH, except for the specific gravity. I don't remember seeing such a discrepancy between the Sp Grav and osmolality before.

One of the sharpest nephrologists on twitter, Christos Argyropoulos, replied with this reference:

The conclusions from the abstract:
RESULTS: This study demonstrated that USG obtained by both reagent strip and refractometry had a correlation of approximately 0.75 with urine osmolality. The variables affecting the correlation included pH, ketones, bilirubin, urobilinogen, glucose, and protein for the reagent strip and ketones, bilirubin, and hemoglobin for the refractometry method. At a pH of 7 and with an USG of 1.010 predicted osmolality is approximately 300  mosm/kg/H(2)O for either method. For an increase in SG of 0.010, predicted osmolality increases by 182  mosm/kg/H(2) O for the reagent strip and 203  mosm/kg/H(2)O for refractometry. Pathological urines had significantly poorer correlation between USG and osmolality than "clean" urines.

Here is a table I made from the conclusions:

Tuesday, September 2, 2014

Sodium, in the spotlight for next week's #NephJC

In August, the NEJM pushed out three articles examining the role of sodium in human disease. These are the subject of September 9's #NephJC.

The first article is the Association of Urinary Sodium and Potassium Excretion with Blood Pressure. This question used the large epidemiologic study, Prospective Urban Rural Epidemiology (PURE) to answer the question.

PURE enrolled 157,543 adults age 35 to 70 from 18 low-, middle-, and high-income countries on 5 continents.

The study collected 102,216 fasting first morning urines. The authors used the Kawasaki formula to extrapolate 24 hour urine sodium and potassium from the samples. They collected 24-hour samples on 1,000 patients and found that they over estimated sodium intake by about 7%:

The mean sodium excretion was 4.9g and the mean potassium excretion was 2.1 grams.
It was difficult for me to understand the difference between the Observed excretion and Usual excretion but the authors seemed to reference the Usual excretion as the definitive curve.

Sodium excretion was higher in rural areas and in lower income countries. The reverse was true for potassium, higher in cities and higher in higher income countries.

The meat of the paper was the positive association between sodium intake and blood pressure. For every additional gram of sodium excretion the systolic blood pressure went up 1.46 mm Hg and the diastolic rose 0.54 mm Hg (P less than 0.001). Statistical mumbo jumbo increased those numbers to 2.11 systolic and 0.78 mm Hg diastolic. This relationship was non-linear with increased blood pressure effect as the sodium excretion rose over 5 grams.

Potassium had the opposite effect with systolic blood pressure falling 0.75 systolic (1.08 after statistical adjustment) and diastolic dropping 0.06 (0.09 adjusted) mm Hg for every gram increase in potassium excretion. 

Older people showed larger changes in blood pressure with increased sodium excretion.

The sodium effect on blood pressure was a lot larger that the 0.94 mmHg systolic and 0.03 mmHg diastolic found in the landmark INTERSALT study but still seems like a pretty small effect given the difficulty in getting to a low a salt diet. Look at the bell curve showing only 0.2% of samples hitting the WHO goal of less than 2.3 g a day.

Sodium, in the spotlight for next week's #NephJC, part 2

The second article in the NEJM package was Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events.

This is an interesting study because so much of the arguments based on salt focus on the intermediate end-point of blood pressure, one can lose sight on the big daddy, total mortality. Previous studies have shown that low sodium diets have paradoxically been associated with higher rates of cardiovascular disease and death. These studies have often been dismissed by sodium puritans by pointing out that including patients with pre-existing cardiovascular disease will pollute the results because these, obviously, high risk patients are told to maintain a low sodium diet.

This study was performed using the same international cohort as the previous trial, The PURE study. This study enrolled 101,945 patients and analyzed early-morning fasting urine samples. They used the same Kawasaki formula that over estimated sodium excretion as in the other PURE study.

They used multiple models to analyze the data.

Patients with pre-existing cardiovascular disease, cancer or events in the first two years of follow-up were excluded from the analysis. They also did an additional analysis using propensity scoring to further reduce imbalanced confounders.

The most important letter in the PURE acronym is P for prospective. In this case it allowed them to match the cross sectional sodium excretion data with long-term follow data. Mean follow-up was 3.7 years. The primary outcome was death or a major cardiovascular event. Over the period covered by the study they recorded 3,317 outcomes. The risk from changes of sodium intake was seen at the edges of intake:
Increased mortality at sodium excretion over 7 grams and below 3 grams

Green indicates an association with sodium excretion. Red indicates no significant association.
The U-Shaped curve seen with sodium was not seen with potassium. The more potassium excretion the lower the risk of the primary outcome.

The results were essentially the same in the propensity-score-matched analysis.

I found this paragraph from the discussion to be particularly salient:
Current guidelines, which recommend a maximum sodium intake of 1.5 to 2.4 g per day, are based on evidence from largely short-term clinical trials showing that reducing sodium intake from a moderate to a low level results in modest reductions in blood pressure. The projected benefits of low sodium intake with respect to cardiovascular disease are derived from models of data from these blood-pressure trials that assume a linear relationship between sodium intake and blood pressure and between blood pressure and cardiovascular events. Implicit in these guidelines is the assumption that there is no unsafe lower limit of sodium intake. However, sodium is known to play a critical role in normal human physiology, and activation of the renin–angiotensin–aldosterone system occurs when sodium intake falls below approximately 3.0 g per day.
The authors make it clear that an epidemiologic association between mortality and sodium excretion is not the same as finding increased mortality or lack of benefit from patients lowering their sodium intake. Advice that the authors of the third study should have taken the time to internalize.
Finally, our study provides an epidemiologic comparison of groups that consume different levels of sodium, and it does not provide information on the effect on clinical outcomes of reducing sodium intake. Therefore, our findings should not be interpreted as evidence that the intentional reduction of sodium intake would alter the risk of death or cardiovascular disease. 

Sodium, in the spotlight for next week's #NephJC, part 3

The last article in NEJM's remarkable sodium package is an extraordinary analysis attempting to estimate the number of deaths that can be attributed to excess sodium intake.

Global Sodium Consumption and Death from Cardiovascular Causes.

The authors reviewed 205 studies of dietary sodium consumption:
  • 142 studies that used 24-hour urine collections
  • 91 with estimates of dietary intake
  • 28 with both methods
These studies came from 66 countries representing 74.1% of the adult population. It is appropriate to whistle and say wow, at this point.

Inorder to translate the sodium intake into mortality the authors first needed to estimate sodium's effect on blood pressure. They employed two Cochrane meta-analysis looking at the effect of reduced sodium intake on blood pressure (Meta 1, Meta 2). They used these meta-analysis to discover sources for there own meta-analysis. They needed age and gender specific effects of sodium on blood pressure which is why they needed to do their own analysis.

After estimating the effect of sodium on blood pressure, they then used the blood pressure data to estimate cardiovascular mortality based on the work done in two large studies (Study 1, Study 2).

Estimated global sodium intake was 3.95 g per day, quite a bit lower than the 4.4 grams measured in the PURE studies. They pointed out that 99.2% of the countries surveyed had mean sodium intakes higher than the WHO level of 2 grams a day. An astounding 88% of the world had sodium intake more than 50% over the WHO recommendation.

Their meta-analysis found that systolic blood pressure fell 3.8 mm Hg for every 2.3 grams sodium intake was reduced. This translates to a more interpretable 1.6 mm Hg for every gram reduction in sodium. This is quite close to the 1.5 mm Hg found in the PURE analysis. They used 2.3 grams because that is equal to 100 mmol of sodium, for people who like to speak like a chemist.

They then ran the blood pressure data into the mortality data from blood pressure and concluded that consuming more than 2 grams of sodium a day results in 1.65 million deaths from cardiovascular disease a year. This is 9.5% of all cardiovascular deaths in the world and nearly 20% of all premature deaths.

However, despite a very through analysis this is an exercise in somewhat meaningless statistical gymnastics. The authors fail to consider the possibility that lowering the blood pressure too far could have negative consequences, (Hello ACCORD Trial. Nice to meet you.) Or the possibility that low sodium diets could be harmful.

Note that, these figures come from a 2011 prospective trial published in a little known journal called JAMA. This signal that low sodium diets may not be beneficial is not new or unknown. It was picked up by the Institute of Medicine in their summary and recommendations to avoid very low sodium diets:
However, the evidence on health outcomes is not consistent with efforts that encourage lowering of dietary sodium in the general population to 1,500 mg/day. Further research may shed more light on the association between lower—1,500 to 2,300 mg—levels of sodium and health outcomes.
This becomes even more concerning when looked at through the lens of the PURE studies in the same issue of The Journal that show average sodium intake to be associated with the lowest mortality and danger rising on either side of the sodium consumption curve.

This is a study best taken with a grain of salt. Couldn't resist.
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