Precious Bodily Fluids

Acid Base for Med Students, a free iBook. Updated x2

2012-01-23T02:13:00.001-05:00

Back in August of 2010 I begged for a content creation system for the iPad and last week Apple delivered iBooks Author.

I just finished converting my Acid-Base handout to the iBook format and the authoring software fits into the rest of the iWork suite. If you know how to use Pages, you will be an iBook Author wiz. The program was solid for a 1.0 release with only one crash in about ten hours of work and I didn't lose any data. I can't wait to dig a little deeper and really build some interactive content. I have a feeling, going forward, that iBook Author is going to be my primary content creation tool. For now check out my first iBook.

Update: Some notes on how to use this file:

You can only use the iBook on an iPad
The iPad must have at least iBooks 2.0 to load the book
The file can be downloaded to a computer and side loaded to the iPad through iTunes, but that seems overly complex compared to just downloading it right from the web sight right on an iPad

Update 2: version of 1.5 is now live with added interactivity.

New Lecture: Initiation of Dialysis

2012-01-20T09:43:00.000-05:00

This is a fellow level lecture. I built it off an old lecture from 2003 or 2004. It is remarkable how much data has emerged since then. Of coarse the IDEAL Trial has put a dagger in the heart of early initiation but the observational data in agreement with abandoning early initiation has also turned.

To fortify this lecture it needs the data on nursing home residents and dialysis outcomes and I'd like to add the recent data on dialysis mortality after the week-end.

All-in-all, its a good foundation.

Initiation of dialysis (PDF, Keynote)

Crazy numbers: largest drop in hemoglobin without a transfusion

2012-01-18T08:07:00.001-05:00

A drop in hemoglobin on 9 grams brings to mind the old surgical maxim "all bleeding stops" but I just had a case of a drop that big that includes three other confounding factors:

He is a dialysis patient
He didn't died
He didn't required a transfusion

He is a 58 year old patient with ADPKD, as part of this disease he had polycythemia and the day he was admitted with a chief complaint of dyspnea he had a hemoglobin of 19 g/dL. He had been advised that this was dangerous and he should go for phlebotomy. Sure enough he had a bilateral PE and multiple DVTs.

We started unfractionated heparin and ordered phlebotomy. So the next morning when we saw the decrease in the hemoglobin from 19 to 14 I was satisfied that he had a good response to phlebotomy. In reality, he never received the phlebotomy.

On that next hospital day he reported worsening flank pain. We ordered a CT to evaluate this and to help evaluate why his PD was failing. Turns out the pain and falling hemoglobin were due to a large bleeding renal cyst and renal hematoma. We stopped the heparin. The hemoglobin fell to 10 g/dL, a tidy 9 gram drop. We transferred him to the MICU. The initial plan was to embolise the bleeding kidney but the hemoglobin stabilized after stopping the heparin. After a few days of expectant testing and nervous observation we resumed the heparin and the hemoglobin held.

While we initially attributed the DVT solely to the erythrocytosis, he has a troubling family history (in addition to the ADPKD) that suggests thrombophilia.

Crowd sourcing nephrology and IgA resources

2012-01-18T08:04:00.000-05:00

I received this letter:

Hi,
I am a patient with IgA nephropathy, (current serum creatinine around 3.7, eGFR around 18ish). I also have an MD from the University of Washington in seattle.

I love your blog. I was wondering if you could recommend books or review-type journal articles on two topics of interest to me. With my MD background I can read fairly technical material, although sometimes get a bit lost in some journal articles. Wanting some overview material to bone up on a few topics.

I just haven't been able to find book titles that seem spot-on. I have a great nephrologist here in Seattle who is very busy at the moment and I can't seem to get his attention via email, etc. to provide these kinds of recommendations. I thought you might be able to help.
1. IgA nephropathy - overview of pathological mechanism, current research areas, etc.
2. A good article/book on reading kidney biopsy results.
Any information would be very much appreciated.

I didn't have anything to suggest. Anyone have any good sources to recommend?

My first post at eAJKD

2012-01-10T10:29:00.000-05:00

As part of my role as a board member of the eAJKD I was able to interview Iain Macdougall regarding his survey of emerging and novel anemia therapies in AJKD. It was a fun interview and I'm proud of how the post turned out. Check it out.

St Clair Specialty Cleaned up in Hour Detroit's Survey of Top Docs

2012-01-10T10:09:00.000-05:00

I work at St Clair Specialty Physicians a nephrology group in Southeast Michigan. In the most recent Top Docs roundup by Hour Detroit, we cleaned up in nephrology with 6 of the 16 selections and also had the top vote getter in hypertension. Great work Drs. Bellovich, Butcher, Khairullah, Provenzano and Steigerwalt.

Crazy Medical Presentation, or Craziest Medical Presentation?

2012-01-09T16:43:00.000-05:00

Giles Brindley, the man who
gave whole new meaning to

PowerPoint.

In 1983 Professor Brindley presented his findings on papaverine injection and erectile dysfunction. His presentation was a bit unconventional as recounted by (PDF) Laurentz Klotz, a senior resident who attended the presentation.

...four or five of the women in the front rows threw their arms up in the air, seemingly in unison, and screamed loudly. The scientific merits of the presentation had been overwhelmed, for them, by the novel and unusual mode of demonstrating the results.

via Andy Ihnotko. Additional and comprehensive coverage at AlignMap

Salty dog, the highest sodium I ever saw.

2012-01-09T16:05:00.000-05:00

A series of sodiums from 176-188 mmol/L

Those are not glucoses. They are Sodiums. And, except for maybe an infant with congenital adrenal hyperplasia when I was a resident, those are the highest sodiums I have ever seen.

The primary management concern was the speed of correction. The first Na at 188 was drawn at 4:32 pm. Four hours later it was 177, a change of 11 mEq. Too fast. Here is the salient section from UpToDate:

Rate of correction in chronic hypernatremia — There are no definitive clinical trials, but data in children (particularly infants) suggest that the maximum safe rate at which the serum sodium concentration should be lowered in patients with chronic hypernatremia is 12 meq/L per day. To be safe, we suggest a maximum rate of correction of the serum sodium of 10 meq/L per day in patients who have had hypernatremia for at least 24 hours. The following findings provide support for this conclusion:
A retrospective case control study included 97 children with hypernatremia and dehydration; the mean baseline serum sodium was 165 meq/L. The rate of reduction in serum sodium was significantly faster in the children who developed cerebral edema compared with children who had no complications following correction of the hypernatremia (1.0 versus 0.5 meq/L per hour).
Similar findings were noted in another report in which the rate of reduction in serum sodium was 1.0 meq/L per hour in the nine infants who developed seizures compared with 0.6 meq/L per hour or less in 31 infants who did not develop seizures.

So Bud Rose, the dean of electrolytes, says 12 mEq per day.

Burton Rose

My patient moves 11 mEq in 4 hours after receiving 500 mL of normal saline. Now what? I was convinced that continuing normal saline would perpetuate the overly rapid correction of the sodium and put the patient at risk of cerebral edema. But since the patient was still in hypovolemic shock, I couldn't just stop the fluids.

I ordered 3% saline. I ran it at 100 mL/hour and 5 hours later the sodium was back up to 186. I was going in circles. I then changed back to normal saline and over the subsequent 48 hours we corrected the sodium at roughly 0.5 mEq/l/hr. The whole time I was going through this I was wondering is it all necessary? Is rapid correction of hypernatremia as dangerous as Rose said it was? Is half a miliequivalent/L/hr a real evidence based speed limit?

I put this question to a fourth year medical student and he did an excellent job diving into the evidence (or lack there of) on the topic. Here is his analysis:

docx | pdf

I think he is a little hard on Rose's guidelines. The student's analysis criticizes one of 4 references that are provided in UpToDate (though his criticism is appropriate and is the sole reference in Rose's landmark Clinical Physiology of Acid Bas Disorders) to support of the 0.5 mEq/L/hr speed limit.

The four UpToDate references are:

Rose's own textbook, Clinical Physiology of Acid Bas Disorders. The page to look at in my 5th edition is 777.
Kahn et al. Controlled fall in natremia and risk of seizures in hypertonic dehydration. Intensive Care Med (1979) vol. 5 (1) pp. 27-31
Fang et al. Fluid management of hypernatraemic dehydration to prevent cerebral oedema: a retrospective case control study of 97 children in China. Journal of Paediatrics and Child Health (2010) vol. 46 (6) pp. 301-3
Blum et al. Safe oral rehydration of hypertonic dehydration. J Pediatr Gastroenterol Nutr (1986) vol. 5 (2) pp. 232-5

I will look at each reference in detail.

The section in Rose's text is very similar to the UpToDate card. The relevant paragraph is on page 777 in my 5th edition (black cover). The sole reference in this paragraph, is the 1986 Blum article (number 4 from the above list).

iPhone, a surprisingly effective photocopier.

Kahn retrospectively looked at the care of infants. They used half normal saline and gave it at 160 mL/kg/day (6.7 mL/kg/hr). All of the patients were 0-5 months, so maintenance fluids would have been 4 mL/kg/hr.

What book did this great page on maintenance fluids come from?

Nine of the first 47 patients developed seizures that could not be explained by other etiologies (fever, hypocalcemia, hypoglycemia) and so were ascribed to rapid fluid restoration, Group I. They matched these nine to 22 age-matched children who were treated contemporaneously but did not have a seizure, Group II. The investigators then changed the protocol for treating infants with hypernatremia to 120 mL/kg/day and included data on 9 patients under 5 months who were treated this way, Group III.

Here is the primary data on the three groups:

All three groups had similar sodiums but Group I had significantly higher BUNs than Group II, with I +II vs III and I vs III being non-signifigant.

The protocol called for patients in Group I and II to get only 160 mL/kg/day. Both groups significantly exceeded this. Group III hit its fluid goal nearly on the nose. They blamed the excess fluid on oral replacement and volume resuscitation with sodium bicarbonate.

The net result was a wide spread in the rate of correction of sodium:

The kids that seized: 1.02 mEq/L/hr
The kids that did not seize but were on the same treatment protocol: 0.62 mEq/L/hr
The kids on the conservative protocol, also without seizures: 0.35 mEq/L/hr

Fang looked at 97 children with hypernatremia. Mean sodium was 164.5. Mean age 13 months. He performed a case-control study with the cases being patients who developed cerebral edema. Manifestations included seizures, eyelid edema, papilledema in all the patients and bulging fontanel in 36 and pupillary abnormalities in 9 cases.

The data shows cerebral edema was more common with bolus therapy, especially when the bolus was faster, higher sodiums were associated with cerebral edema but much of that disappeared in multivariate analysis as higher sodiums were also associated with increased rate of correction and ind increased bolus rates. Using ROC the investigators found a rate of fluid administration of 6.8 ml/kg/hr was safest. And the average decrease in serum sodium in the cerebral edema group was 1 mEq/L/hr and 0.5 mEq/L/hr without cerebral edema.

The final reference is Blum's study of oral rehydration, this is the reference my med student was upset with. As he outlined, this was a study of oral rehydration rather than a study of rates of treatment. The cohort was composed of eighteen infants, 6 months or younger admitted with hypernatremia (Na > 150) and treated with oral fluid resuscitation. They compared the hypernatremia outcomes to a second cohort of 26 infants who received IV rehydration for hypernatremia. Average sodium for both groups was 160.

In both groups the reduction of sodium was slow (0.3 mEq/L/hr) and no patient developed seizures.

In Burton Rose's Clinical Physiology of Acid-Base and Electrolyte Disorders this observational study with no seizures is the sole reference behind the recommendation for a slow restoration of normal sodium. Weak sauce. Of note Androgue's review of hypernatremia in the NEJM from 2000 references the same Blum and Khan articles to support its recommendation of slow treatment.

So in the end, the recommendation for slow normalization of sodium is based on a handful of studies in infants with no randomized or even prospective studies. What is unbelievable to me is no one references a study that reviews the functional/neurological outcomes of patients with the highest sodiums admitted to a large hospital based on the speed of correction. Seems like an easy study and in its absence we are left to trust in the physiology of babies.

My Apple Predictions. 2012 edition

2012-01-05T16:30:00.000-05:00

Last year I published a list Apple predictions and I will post a complete score card. However, some of my predictions can not be judged until Apple announces its first quarter results on January 24th. I will however provide my 2012 predictions now.

iPad
The iPad 3 will be announced February 28th and released March 16th. The iPad 3 will include a Retina Display with a resolution of 2048x1536. The case will largely look like the current iPad but Apple will introduce colors (again) like the iPod Nano and possibly patterns like the old Flower Power and Blue Dalmatian iMacs.

The cellular equipped iPad 3 will come with LTE radios in addition to the 3g and 2g radios they currently have. The large battery capacity of the iPad will make this luxury a possibility even though the iPhone 5 will lag behind with 3g.

The iPad 3 will also have the new quad-core A6 processor and get the same battery life as the current iPad except when using the LTE radio.

The memory options will remain16, 32, and 64 gb. This will be the last iOS device to include the 30 pin dock connector. The iPad 3 will get Siri. Prices will remain the same.

The current iPad 2 will continue as a discount model to fight the Kindle Fire and what-ever 7 inch piece of crap Eric Schmidt is talking about. The iPad 2 will only be available in 16 gb, but will still be available with WiFi or WiFi +cellular. The iPad 2 will be priced at $349 for the WiFi version and $479 for the WiFi +cellular

In addition to Verizon and AT&T, Sprint will get both iPads. Sprint will introduce a discounted price that bundles the wireless internet for your phone and iPad in order to solidify its position as the bargain wireless plan.

Last year I estimated cumulative sales of 65 million iPads (total of 2010 and 2011 iPad sales). Barring a total sales frenzy over this past Christmas I'm was a wee bit optimistic, with cumulative sales coming in closer to 54 million (that assumes iPad sales of 14 million in the Christmas quarter, 90% more than last Christmas, and 30% more than previous quarter). I am going to predict sales of 60 million iPads in 2012.

iPhone
The iPhone 5 will be introduced in September and go on sale two weeks later. The message of the design is durability. Apple will use the same nano-coating that Motorola used on the RAZR to make it more water repellant. Apple will brand this with a unique name and claim it to be a major breakthrough.

Continuing with the theme of durability, Apple will abandon the 30-pin dock connector and seal the entire body of the phone. All data connections will need to be done wirelessly. A new MagSafe-like connector will be introduced for charging. Additionally the iPhone will lose the glass back, and it will be replaced with an aluminum one like on the iPad.

NFC will be added to go along with an electronic wallet system called iCash. This will be linked to your iTunes account.

The phone will be slightly thinner than the iPhone 4, but will largely have the same form factor. There will not be a tear-drop shaped design. The screen size remains 3.5 inches. Like the iPad 3, it will be released in multiple colors. The rear camera gets better, the device gets thinner, the phone receives the quad core A6.

With the introduction of the iPhone 5, the iPhone 4S is only offered with 16 gb and moves down to $99. The 8 gb iPhone 4 becomes the free offering in developed countries and the 3GS soldiers on as the price leader in emerging economies.

Last year I predicted Apple would sell 65 million iPhones. As of September 1, Apple has sold 56 million and analysts are expecting 30 million in the Christmas quarter, for a total of 86 million iPhones. So I blew that. 86 million represents an increase of 181% over 2010, which was an 189% increase over 2009 which was an increase of 183% over 2008. I'm going to guess that iPhone sales continue this incredible streak and grow by 180% in 2012 so that is 154 million. My official guess is 160 million iPhones in 2012 (that seems totally insane given that Apple has cumulative sales of 146 million iPhones as of September 2011).

Data from Asymco.

iPods

After a stale year with no changes besides a white iPod touch the iPod line gets a significant revision.

In October, a month after the iPhone announcement, Apple will unveil the new iPod lineup. It's tag line will be something like "Something big. Something small." The iPod Nano is the something small. It adopts iOS and becomes the smallest general purpose computer. Like the iPhone it will lose the 30-pin doc connector while gaining WiFi and bluetooth. Apple will open the Nano to a specialized corner of the App with simple single function apps that incorporate voice control and feedback. The Nano will also gain a front and rear facing camera. Yes I know this is exactly what I predicted a year ago, but in the grand-tradition of Apple prognostication, I wasn't wrong, just a year too early.

The iPod touch goes big. It gains a 4 or 4.5 inch screen and is marketed as a game machine and Kindle competitor. It bumps up to the A5 processor and remains just as thin as the current device. The front face gains multiple colors but the back remains polished stainless steel. It also loses the 30-pin dock connector. All of those sightings of a teardrop shaped, 4-inch screened iPhone 5 from last summer were actually early proto-types of the 2012 iPod Touch.

Apple offers an iPod Touch with a cellular radio for the first time, just like in the iPad. The data rates are also identical to the iPad. No LTE option. Prices:

8 gb WiFi $229
32 gb WiFi $329 WiFi + Cellular $399
64 gb WiFi $429 WiFi + Cellular $499

iOS

iOS 6 is announced at WWDC in June and roles out to all iOS devices in September a week before the introduction of the iPhone 5. The marque feature of iOS6 is Siri which becomes available on the iPhone 4, iPod 4th Generation and all three iPads. Siri leaves beta and opens up to allow limited third party software access to new voice and speech APIs. TV shows and movies get the iCloud experience and can be downloaded repeatedly. FaceTime over 3g.

Macintosh

The big story of 2011 is the repositioning of the MacBook Pro line. After the MacBook Air displaced the MacBook in 2011, it will set its sights on the iconic MacBook Pro. The MacBook Pro 13 inch will disappear entirely. The 15 and 17 inch will remain.

The Macbook Air line will add a 15 inch model. The MacBook Airs will begin to offer a cellular modem option.

MacPro will get updated without fanfare in March. Despite much handwringing, this will not be the final update of the tower mac which continues to serve a small, but influential, sliver of the Macintosh family.

Apple will introduce a cloud back up service which will move Time Machine from a spare drive on your desk to one of Apple's data centers. This will be a pay-to-play service: one year of back-up will be provided with new machines and it will be $100 per year after that.

Throughout 2012 there is not a peep about the next version of OS X.

Apple TV

Apple introduces a revamped Apple TV at WWDC and it goes on sale in September. It remains the little iOS box that is currently sold with a bigger processor and a new version of the OS and Siri. An iOS device running iOS 6 will be required to act as the microphone for Siri. It will also gain the ability to add apps from the iTunes App Store. The Apple TV Set will also be introduced in June for a September or October role out. The Apple TV set (iPanel?) will not offer any significant feature beyond the Apple TV. However, it will come bundled with a 7 inch iPad to act as a remote control, game controller and auxiliary screen. Additionally, any iPhone, iPad and iPod running iOS will be able to duplicate the functions of this uber-remote.

Apple

Apple will spill some of their massive war chest to lock-up exclusive content deals. This will include sports, movies and original content. They will continue to purchase small engineering-focussed companies but no other major merger.

Tim Cook will remain the CEO and there will be a steady trickle of VPs leaving the company for other CEO positions. Names that will stay include Cook, Cue, Ive and Schiller. Forstall, Mansfield are among the Veeps who may move on.

A lot of companies might try to entice the architect of the iPhone to be their top guy and with a young Tim Cook (born 1960) secure as CEO, an ambitious Forstall might make the jump. Can you imagine Scott Forstall being tapped to replace Ballmer at Microsoft?

With the release of the new Apple TV the stock will be seriously goosed. I expect a 52-week high of $667 and the stock to close 2012 at $605.

John Gruber, a closet reader of PBFluids?

2012-01-03T14:32:00.002-05:00

Take a look at my post on Andy Warhol, Coke and the iPhone

And now, Gruber's post on the same subject.

One time. Just one time, I want to get linked by Gruber.

Coffee + MacBook Air = No posts for awhile

2012-01-03T11:33:00.005-05:00

I spilled an entire cup of coffee on my laptop.

Dead laptop.

Last back-up, 7 weeks old.

Lost blogging momentum.

I have a pile of half written posts and should be out of the funk soon.

I have also purchased a dropbox account and will not be caught with two-month old back-ups again. That's a pretty good new years resolution, though better would be to not spill cups of coffee into my laptop.

New medical blog

2011-12-14T23:33:00.002-05:00

Kamran Boka, a resident at St John's wrote an excellent on-call manual. It has been released under creative commons license.

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License.

Free to share and free to make derivative versions, with attribution. The manual is nicely put together and you can find the PDF at his blog, Vagal Thoughts.

AASK: a cautionary tale for bardoxolone?

2011-12-12T22:55:00.000-05:00

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.

Brilliant little video on exercise

2011-12-12T17:05:00.000-05:00

My pithy little push for exercise is that it is the closest thing we have found to the fountain of youth. That it doesn't mater what disease you look at, increasing you exercise or fitness is associated with better outcomes.

Love this video.

Less medicine, better care

2011-12-12T08:19:00.001-05:00

Thought provoking article at Zocalo Public Square by Ken Murray a family practice doctor who writes that he was so frustrated with futile end-of-life care he suspended his hospital practice.

Of course, doctors don’t want to die; they want to live. But they know enough about modern medicine to know its limits. And they know enough about death to know what all people fear most: dying in pain, and dying alone.

The essay feels right but relies on anecdote rather than data to support the central premise that doctors are more likely to to use hospice and palliative care to have gentler passing.

Diabetic nephropathy

2011-12-09T22:50:00.001-05:00

I was invited to do grand-rounds at St John and was given no guidance on selecting my topic. I recently received a phone call from a long-time family friend, this man had literally changed my diapers, and he asked me to help a relative get bardoxolone. My group is participating in Beacon (the current phase II trial for bardoxolone) and though I am not one of the investigators I assured him that we would evaluate his friend. I couldn't guarantee he would get study drug rather than placebo or even qualify for the trial.

The whole event shocked me. I had no idea that the results of the Bardoxolone study had slipped beyond the geek fringes of nephrology. It reminded me of a story that Judah Folkman told. He came to Indiana University to collect an award and give a lecture, shortly after a NYTimes profile. In that front page story James Watson (yes that James Watson) said Folkman would cure cancer in two years.

Judah told the story that he was getting phone calls from strangers and friends asking for his miracle cure and was heart broken because he had nothing to offer them. At that stage his drug was only for mice.

That's Judah and me following the afore mentioned lecture in 1999.

Getting that call from my friend gave me the same sort of Folkman moment. I never thought people would be calling me trying to get experimental therpy. So I decided to talk about Bardoxolone.

As I started my research I became concerned that patients randomized to bardoxolone developed increased albumniuria.

Some patients tripled their albuminuria! The drug increased GFR, but the increased albuminuria could not be fully accounted for by the improved function.

ASN Kidney Week fell 10 days prior to my Grand Rounds so I planned on grabbing some good ideas at the meeting. On Friday I went to Kidney Disease in Type 2 Diabetes: New Insights. There were four lectures. The last two were homeruns.

Dr. Bruce Perkins was perfect for my talk. He spoke of how albuminuria is not a great surrogate end-point for diabteic nephropathy studies. Bad outcomes often follow a reduction in proteinuria.

I used my iPhone to record the audio and took pictures of each slide with my Nikon (this was before I learned that ASN did not want attendees taking pics of the lectures. WTF). When I got home I grabbed the best thoughts from his lecture and made it the cornerstone of my talk on diabetic nephropathy, bardoxolone, and a more modern view of albuminuria.

Thanks Dr. Perkins.

The lecture was a little light, I finished in 45 minutes and used some filler from my Diabetic Nephropathy 2009 lecture. Before I use the lecture again I would add some of the points from Andrew Bomback's excellent lecture, "RAAS Blockade: More is better? Yes. No. It depends."

Here is my PowerPoint (58mb) and PDF (51mb).

Note to self: the Helvetica Neue UltraLight, didn't project so well.

We've got one! Finding a functional adrenal adenoma

2011-12-05T10:20:00.001-05:00

A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.

The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.

One of the findings that stood out for me was the hypokalemia on the initial labs

We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was "real" and after that she was compliant with the medical therapy.

The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:

Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.

Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.

The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt

An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:

aldosterone in nanograms per deciliter
renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour

With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn't meet the criteria for primary aldosterone is not important to me because I'm going to treat both of those conditions identically, with spironolactone or eplerenone.

So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.

Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:

Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.

The authors did not provide a 2x2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:

Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives

The two-way table looks like this:

What? You're still using Epocrates' medical
calculator? Don't be a tool, get a tool, MedCalc

It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.

We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.

She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.

The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.

Water humor.

2011-11-30T23:56:00.001-05:00

Inorganic chemistry jokes: rare and rarely funny.

And the data keeps rolling in...

2011-11-09T08:00:00.000-05:00

I am a believer in Richard Johnson's theory regarding fructose uric acid and hypertension/CKD. So I love it when I see another study adding to the foundation. This from Diabetes Care. The investigators looked at 1500 patients with diabetes and normal renal function and no proteinuria. Over 5 years they tracked who developed CKD (either GFR<60 or proteinuria):

During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD.

the iPhone as tricorder

2011-11-08T22:34:00.000-05:00

Looks like bubble-mania to me. What do you think?

Via Brian Hall's Smart Phone Wars

Write your own text book, save money

2011-11-08T14:31:00.002-05:00

I bet this becomes a real trend as school districts become short for cash.

Anoka-Hennepin teachers write their own online textbook, save district $175,000

Instead of mass-produced textbooks, the more than 3,100 sophomores in the state's largest district are learning from an online curriculum developed by their teachers over the summer with free software distributed over the web.

For the extravagant tuition charged at medical schools it seems they should throw in the course materials for free. No?

Dynamed versus uptodate

2011-11-08T08:00:00.001-05:00

I received the following announcement from our hospital librarian

We are conducting a trial of the online clinical resource Dynamed for the month of November. We wanted to get some feedback on this product as an alternative to UpToDate, or possibly as an addition to our electronic resources before we negotiate with UpToDate.

So to check it out I did a quick tour of UpToDate and then the same tour on DynaMed. I recently diagnosed a patient with Goodpastures so I looked that up in both databases.

UpToDate

UpToDate has a great autocomplete system for search terms. Not sure if Goodpasture is one or two words? Don't worry, typing "Good" is good enough.

The number of topics on Goodpastures is remarkable.

I love how the topic outline slides opens on the right when you hover over a topic. When I selected Treatment of anti-GBM antibody (Goodpasture's) disease I was treated to 3500 words (excluding references, of which there were 32) written by an editor team that puts their name to the review. In this case the authors are all tops in glomerulonephritis:

The article is long, detailed and tells the reader exactly how to treat the patient. What drugs, alternative treatments, how to pheresis including replacement fluid, schedule, dose and duration. It is beautiful in its completeness.

DynaMed

I typed in Good, no autocomplete at all. I searched Good and good pastures is not on the first page of search results.

I searched Goodp and got nothing.

Searched Goodpastures and...jackpot! They even have the roll-over see the outline trick from UpToDate. Nice

The actual article though, is terrible compared to UpToDate. They have a single entry on Goodpastures which is barebones outline of the condition.

The treatment section contains 159 words, and really gives you no idea how to treat this condition. In fact, about a third of the treatment section is dedicated to combination ACEi and ARB therapy, a window dressing issue in the treatment of this rapidly progressive and potentially fatal disease. I would give this reference a failing grade. You read all 159 words and have no idea what to do. You need to go to a second source.

Their is no author associated with the outline of Goodpastures. Dynamed's editorial team does not list any nephrologists. The editorial board does have a single nephrologist, which is exactly how many podiatrists they have on the board.

As my colleague, Dr Steigerwalt, said, it should be spelled DinoMed as in Dinosaur.

AJKD launches a blog

2011-11-07T23:52:00.000-05:00

Say hello to eAJKD. Kenar Jhaveri of Nephron Power is the editor and he has enlisted much of the nephrology blogosphere, including your humble author to assist him on this endeavor.

Recently some of the all guard of media have started compelling blogs (see the New York Times' page of blogs for an example). Medical publishing seems to have lagged in this phenomenon.

All of the interesting medical bloggers are independent agents, though The Lancet, JAMA and NEJM have all launched blog initiatives.

I hope that eAJKD aspires to be something special, I'll do my best to assist it.

It should be a fun adventure.

Crazy numbers: the lowest hemoglobin I have ever seen

2011-11-07T10:00:00.000-05:00

When I was a resident I saw a really low hemoglobin. I don't remember what the number was but I remember the circumstances. I was working the ER at Riley Children's hospital and EMS pulled up with a infant who was short of breath. The family had been feeding him cows milk instead of formula and as a result he had severe iron deficiency anemia. Great case and after a few transfusions and some parental education, everyone lived happily ever after.

Last week I saw another lowest hemoglobin. Since I wasn't blogging when I was a resident I don't know if this hemoglobin is lower than that poor kid but here it is:

Hemoglobin of 3.6 g/dL. The hematocrit is still a double digit number, but still that's a really low hemoglobin.

This is a dialysis patient who started having some vomiting that looked a little "dark" but didn't really bother him. A day or so later he developed some dark colored diarrhea. Still didn't bother him. Then he found himself short of breath, like he missed a treatment and got volume overloaded. This kept getting worse so he finally decided to get in his car and drive to the ER. The admitting hemoglobin was 3.7 followed by a repeat by I'm sure a disbelieving ER doc.

Diagnosis duodenal ulcer and after a half dozen transfusions and a prescription for BID omeprazole he was discharged home to lived happily ever after.

Articles that changed the way I practice: ACCOMPLISH

2011-11-04T08:00:00.000-04:00

I was searching PBFluids and could not find any posts about ACCOMPLISH which surprised me. I then went to the Renal Fellow Network and found a similar lack of commentary. Dito for Nephron Power, and Nephrology on Demand. Even The Kidney Doctor with 100+ posts (and in the process putting the rest of the nephrology blogosphere to shame) in the last 2 months comes up empty handed.

Now some of this may be due to faulty blog search and some of this may be due to the fact that the study is approaching 3 years of age, but regardless ACCOMPLISH is important enough that it should get higher profile coverage.

The study was published in the NEJM in 2008

The acronym is an obviously:

Avoiding
Cardiovascular events through
COmbination therapy in
Patient
LIving with
Systolic
Hypertension

From the title, if not the acronym, the point of the study should be clear: The study pits benazepril and amlodipine (Lotrel) against benazepril and hydrochlorothiazide (Lotensin).

The politics of this fight are interesting as this study tries to right one of the possible mis-steps in the wake of ALLHAT. ACCOMPLISH used the thiazide diuretic that is actually most often used in the U.S. and the only thiazide that is used in combination pills, hydrochlorothiazide (yes I know I'm ignoring Tenoretic, atenolol and chlorthalidone, but every other combination pill uses hydrochlorothiazide). ALLHAT used chlorthalidone as its diuretic and when this largest-ever hypertension study concluded that there was no difference among chlorthalidone, amlodipine and lisinopril on fatal coronary heart disease and non-fatal heart attacks, thiazides became institutionalized as the primary agent to treat hypertension.

Figure depicting the primary outcome from ALLHAT

The money shot from JNC7 (pdf) institutionalizing thiazide-type diuretics

The problem stems from the fact that hydrochlorothiazide and chlorthalidone are unique molecules with significant biologic and pharmacokinetic differences.

This year Dorsch et al re-analyzed data from the MRFIT trial. This was a long-term primary prevention trial from the 70's that changed protocols mid-stream and converted patients from HCTZ to chlorthalidone. This allowed Dorsch's team to look for differential effects of the two diuretics. They found a 21% reduction in cardiovascular events with chlorthalidone:

If you are interested in the reasons behind the differences read John Flack's editorial associated with Dorsch's analysis and look at a 2004 review by Carter et al.

So ACCOMPLISH set out to show that the ACEi CCB combination is superior to the ACEi HCT combination. They randomized 11,506 patients to one of these two arms. The dosing titration seems fair:

20 benazepril and either 5 of amlodipine or 12.5 of dydrochlorothiazide
if BP is not < 140/90 (130/80 in CKD and DM) increase to 40 mg of benazepril
if BP is not < 140/90 (130/80 in CKD and DM) increase to 10 of amlodipine or 25 of hydrochlorothiazide
if BP is not < 140/90 (130/80 in CKD and DM) add additional agents as needed

The cohort was rather sick with previously diagnosed hypertension and an additional history of at least one of the following:

Coronary events
Impaired renal function
Peripheral artery disease
LVH
Diabetes.

The end point was time to first cardiovascular event, or death from cardiovascular disease.

The study was well run but the blood pressures were not perfectly equal between groups with a small but statistically signifigant difference in the blood pressures between the two groups:

131.6/73.3 in the Benazepril-Amlodipine group
132.5/74.4 in the Benazepril-Hydrochlorothiazide group
A difference of 0.9/1.1 in favor of the Benazepril-Amlodipine group

The study was terminated early because the data and safety monitoring committee observed a difference between the two groups that exceeded the pre-specified stopping rule. They found a 20% risk reduction in only 30 months. This represented an absolute risk reduction of 2.2% which translates into a Number Needed to Treat of only 45.

Entering EBM free zone:

To my eyes, ACCOMPLISH better represents the patients I see than ALLHAT. All of the patients that come to my CKD clinic have high blood pressure and almost all also have the additional co-morbidities needed for enrollment. After fully digesting ACCOMPLISH I have made two changes in my practice pattern:

I am starting patients with ACEi + CCB or ARB + CCB. I have been impressed by the effectiveness of Lotrel and Exforge as single pill solutions to a lot of hypertension.
I avoiding hydrochlorothiazide where ever possible. This usually requires re-jiggering a number of medications but a common switch will be to move patients from a list that looks like this:

Lisinopril HCT
Amlodipine

To a list that looks like this:

ACEi CCB combination pill
Chlorthalidone

This results in significant improvement in blood pressure control.
I have to thank ACCOMPLISH to opening my eyes to this change.

Nephrology blog-together at Kidney Week

2011-11-03T22:10:00.000-04:00

Next week is ASN's Kidney Week in Philadelphia. Some of the kidney bloggers are going to be getting together to clink glasses and talk blogging, kidneys, MedEd and whatever else spills from our lips. We are meeting at McGillin's Olde Ale House.

When you get there look for the nerdy guys who look like they spend too much time staring at an screen.

Friday, November 11th at 8 pm
McGillin’s Olde Ale House
1310 Drury Street
Philadelphia, PA 19107
215/735-5562
www.mcgillins.com

Hope to see some of you there, and remember when you are tweeting about Kidney Week use the hashtag #kidneywk11

No! No! No! Never! Give a dialysis patient a Fleets Enema!

2011-11-03T08:39:00.000-04:00

What is wrong with this picture?

Sevelamer and Fleet Enema. They go together like a honey baked ham and Chanukah. Fleets enemas have an obscene amount of phosphorous and sevelamer (Renvela) is a phosphorous binder. They should never co-mingle on the same MAR. So while some may see a couple of benign medications, I see a Chanukah ham.

A Fleets enema, or any typical sodium phosphorous enema, is roughly 4 onces or 120 ml. The active ingredient is sodium phosphorous, to the tune of 26g of sodium phosphate per dose, some articles quote a phosphorous concentration of 13,000 mg/dL. Remember, a normal diet has about 1 gram of phosphate and only 700 mg of that is actually is absorbed; so we are talking about a potentially massive overdose.

I love that someone scanned the entire packaging

No patient with kidney disease or on dialysis should get this drug without talking to their doctor. Its written right on the damn package.

I guess, if you are in the hospital and the doctor orders it, that is essentially the same thing as asking your doctor. Too bad that over and over again doctors express their ignorance about dangerous this seemingly innocuous medication can be by ordering it in patients with kidney disease.

A rogues gallery of bad outcomes from the lowly Fleets Enema

The sodium phosphorous enema can be lethal to a patient with kidney failure.

Here is a case report regarding a patient who developed hypocalcemic tetany and coma following a single enema

My favorite quote in the case report is the hyperphosphatemia review of systems:

...the family denied that other drugs or unusual food such as star fruit was given by them- selves.

They gave the patient a couple of amps of calcium gluconate and then dialyzed him on hospital day 6, 7 and 8.

The situation is even more harrowing if you give the enema orally. This results in massive sodium and phosphorous absorption. In this case report the team gave it to the patient...twice:

They ran in to trouble while treating a toxic theophylline level. They gave activated charcoal to bind the theophylline. Subsequently, the patient developed an illeus and was given 120 mL of a sodium-phosphorous enema down the NG tube. The next day he received 4 liters of polyethylene glycol via the NG and finally another 120 ml sodium phosphorous enema enterally.

Then he arrested.

They resuscitated him. Here are his post-code labs:

Na 177
K 2.8
CO2 18
Cr 3.4
phosphate 59.6
calcium 5.2
Ca x Phos product: TFTC*
pH 7.12/37/40

* Too frightening to calculate

After resuscitation the patient was too hemodynamically unstable for dialysis and died during a subsequent arrest.

Look at that phosphorous! A phosphorous over fifty is like a traffic accident, can't tear your eyes away.
Here's a simple rule:

If the medicine is supposed to go in the butt, don't feed it to your patient.

As high as the phosphorous is however, the symptoms are due to the low calcium. The high phosphorous complexes with the calcium driving the ionized calcium down.

Severe hyperphosphatemia and hypocalcemia: a dilemma in patient management

JASN published a tight review in 1996. They discuss an unfortunate case where a gentleman was prescribed two enemas for a flexible sigmoidoscopy prep. The patient however, mistakenly ingested them orally rather than, you know, using them the right way. 191 mmol of sodium and 208 mmol of phosphorous down the hatch. The patient presented to the ER complaining of foot and hand pain along with diarrhea and difficulty swallowing and speaking. Data on presentation:

QTc 0.6 sec (prolonged)
ionized calcium 0.34 mmol/L
total calcium 4.5 mg/dL
Na 154 mmol/L
phosphate 44.8 mg/dl
anion gap 39

The patient was managed with insulin and dextrose, aluminum hydroxide and IV calcium gluconate along with IV fluids. Dialysis was delayed for 4 hours due to difficulty gaining IV access. He was dialyzed against a high (3.5 mg/dl) calcium bath

One of the points I tried to highlight in the graph is the rapid drop in the phosphorous prior to the dialysis. The conservative therapy of IV fluids, insulin, and aluminum hydroxide look highly effective. Also note how effective dialysis is at raising the calcium.

The authors make an excellent point regarding the acidosis. The patient had an initial pH of 7.28 and an anion gap of 39. The anion gap is from the high phosphorous. The authors point out that treating the acidosis with alkali will further drop the ionized calcium and is contraindicated until the calcium is corrected.

The discussion of the paper is delicious and addresses a situation I have found myself debating with fellows. The question is what to do when the phosphorous is really high and the patient has hypocalcemic symptoms. Does the administration of calcium lead to metastatic calcification to the detriment of the patient? The authors feel that calcium should be given to treat the symptoms of hypocalcemia and delay full treatment of hypocalcemia until the phosphorous is restored to normal levels.

In terms of personal experience, the MAR from the top of the post comes from a dialysis patient who did receive a Fleets enema while in the hospital. His phosphorous went from 3.5 to 11.7, overnight. He remained asymptomatic but the whole experience terrified me.

No. No. No Never. Give a fleets enema to a dialysis patient.

Pica or a novel fluid management strategy?

2011-10-25T01:09:00.002-04:00

One of my favorite patient is a chronic fluid abuser. Today on rounds I noted that she had been doing better with this. She proudly showed me her new way of coping...rocks.

She is sucking on rocks rather than drinking. It takes all types.

If you ever get a chance to hear Ridley Baron don't miss it.

2011-10-24T13:46:00.000-04:00

A few weeks ago my hospital brought in Ridley Baron, a pastor who underwent a terrible tragedy that subsequently became even more horrific due to a medical error.

Here is a peak at his talk, I wish he would put more online, but he has his reasons for not doing it.

A Victim's Perspective on Quality Care from Ridley Barron on Vimeo.

He does a great job of letting healthcare workers glimpse what the hospital experience is from the eyes of the victims. Inspirational.

Blogging as an academic endeavor

2011-10-21T10:31:00.003-04:00

From Skeptical Scalpel (twitter)

Since I dropped out of the business of training residents, I have been actively blogging and not cranking out mindless publishable research. Here is an interesting fact. I have no doubt that far more people have read what I have written in my blog for a year and a half than ever read all of my 95 published works combined.

Sing it brother! It takes me about a hundred hours to prepare a de-novo talk for grand rounds. I will then deliver it to an cohort of 50-80 docs with a collective GCS of 10. After the last audience question the lecture video will be filed in the medical library never to be found again. The lecture is not searchable or discoverable and the work is largely lost.

An average post at PBFluids will get more views than the grand rounds in the first few days and if it is linked by RenalWeb other aggregator it will get enough page views to fill one of the great conference halls of the national meetings. After the first week the post continues to be an eternal flame of searchable and discoverable data. To me the relative impact tips way toward blogging as a more significant form of academic communication but to the powers that grant career advancement it is a meaningless toy.

Fading gross hematuria after kidney biopsy

2011-10-18T10:31:00.001-04:00

- Posted using BlogPress from my iPad

Dogs, squirrels and evolution

2011-10-09T22:09:00.000-04:00

This is my dog Bo.

Bo is a Woodle. I wanted to name him Chewbacca.

He loves to chase squirrels.

On google image search the top suggested related-search for squirrels is squirrels with guns

He was chasing squirrels all over my neighbor's lawn, much to the delight of the 6-year old twins that live there. I proceeded to tell them the story of the only time Bo caught a squirrel.

I was jogging with Bo and he saw a squirrel. He chased the rodent for 10 feet until the squirrel climbed a tree. Bo looked up the tree and tried to jump a few times but the squirrel was too high. I told Bo that maybe he'd catch the next squirrel and we started to run down the block. Then the squirrel fell out of the tree and landed right in front of Bo. Well, Bo grabbed that Squirrel in his jaws and killed it faster than you could say "rabies shot." It happened so fast all I could remember was the sound of his little lungs being punctured by Bo's teeth. (Six year olds love the gory details. Bilateral pneumothorax, gotta be a quick way to die.)

Then I asked the twins, do you think that squirrel was a good climber?

They answered, "No."

Do you think that squirrel's babies would be good climbers?

They answered, "No."

Do you think that squirrel is going to have any more babies?

They answered, "No."

That's why squirrels are so good at climbing trees. The ones that are bad at climbing, die and can't have babies. We call that evolution.

And I call that a teachable moment.

Come on America, Its not that hard.

Gallup Poll Feb 2009

Level of support for evolution from wikipedia

Doctors are like the pyromaniac fireman

2011-10-09T13:25:00.000-04:00

A patient, on Friday, explained that doctors are like the pyromaniac fireman who when he's not putting out fires is secretly setting them so he can fight them.

Ridiculous?

Well, on that same day I saw a patient who previously had uncontrolled blood pressure. I had gotten her blood pressure under control with a combination of torsemide, spironolactone, carvedilol and amlodipine. Her office blood pressure was 123/72 with a heart rate 86. During the visit she told me that she had fallen three times in the last few weeks. Her standing blood pressure was 96/53 with a heart rate of 96. On her previous visit I had extinguished and set a new fire at the same time. Her previous blood pressure had been in the 150s. Controlling her blood pressure was the right thing to do medically but undoubtably it was the cause of her recent falls and my attempt to trim long term morbidity resulted in her being exposed to increased short term morbidity.

Pyro fireman.

Another patient I saw has advanced diabetic nephropathy, CKD stage 4. He needs an ACE inhibitor or an angiotensin receptor blocker to stave off dialysis, unfortunately he cannot tolerate them because of recurrent of hyperkalemia. A few months ago I added a loop diuretic to control edema and hypertension and a couple of weeks ago he returned for a follow-up. His potassium was 4.6 mmol/L. The loop diuretic had increased kaluresis enough that I felt that I had some room to give another trial of renin-angiotensin blockade. Yesterday I received a call informing me of a critically high potassium in this patient.

Pyro fireman

These cases are not limited to clinical medicine, the ACCORD trial tried to determine if normalizing the Hgb a1c in diabetics reduced cardiovascular mortality. Better diabetic control caused increased total mortality.

In OnTarget the combination of an ACE inhibitor and an angiotensin receptor blocker was tested to see if it could reduce cardiovascular events. The combination was a favorite among nephrologists as a way to stave off dialysis in patients with persistant proteinruia despite single drug renin-angiotensin blockade. Dual blockade was the fashion mostly in response to the subsequently retracted COOPERATE trial. In OnTarget there was significant increase in renal dysfunction with dual ACEi/ARB and a trend toward increased dialysis:

"...whereas the rate was increased in the combination-therapy group, with 65 patients (0.8%) undergoing dialysis"

Pyro fireman, academic style.

It's what makes medicine so difficult, the more you try to help your patients the more you expose them to unintended, adverse reactions. I feel that so little of medical education prepares us to balance these competing end-points, how do you judge what is an acceptable risk of hyperkalemia, how do you balance the risk of hypertension versus the risk of orthostatic hypotension?

Fellow-level lecture on urea kinetics

2011-10-06T22:16:00.000-04:00

I reworked an old lecture from '05 on urea kinetics. The old lecture had a hideous purple background, so changing that to black would have been enough but I added a number of cool touches to fully update it. It worked pretty well, though the end's pacing is off.

PowerPoint | PDF

I especially like the sequence walking through using the iPhone to calculate the simplified single pool Kt/V. Its amazing how many people don't realize that turning the calculator sideways brings up scientific functions. I love watching their faces light up when I say, "Now turn it sideways."

The lecture uses the three randomized controlled trials on dialysis to introduce and explain the three varieties of Kt/V:

NCDS: to discuss single pool Kt/V
HEMO: to discuss equilibrated Kt/V
Frequent Hemodialysis Network in center study: to discuss standard Kt/V

I have another hour long time slot in December to talk about dialysis prescription. I'm going to discuss the recent data on dialysis interval and mortality.

What else should I talk about?

Steve, you put a dent in the universe

2011-10-05T21:46:00.000-04:00

The link is to Apple.com
Google, keeping it classy

jonathon mak

Brian Lam on Steve Jobs during the lost iPhone 4 story

Flags at 1 Infinite Loop

Steve and wife, Laurene, after his last product introduction, WWDC 2011 iCloud

John Siracusa's touching remembrance

In the official version Richard Dreyfus is the narrator. I had never heard this version with Steve at the mike.

Egg Freckles is a Apple website, the term is from a Doonesbury comic poking fun at the Newton's terrible handwriting recognition.

Gruber, always subtle, changes the background of Daring Fireball to a darker, almost black, grey.

Kidneys from Tiffany's

2011-10-05T00:42:00.002-04:00

Check it out

Hat tip to @okarol

Renal Fellow Network: deep dive on urea kinetics

2011-10-04T23:10:00.002-04:00

Graham Abra did a nice series on the urea kinetics of dialysis

The agony and ecstasy of of secondary hyperparathyroidism

2011-10-03T09:03:00.000-04:00

Managing secondary hyperparathyroidism in dialysis patients should be a rewarding aspect of nephrology. I thrive on complex management that involves balancing various numbers with clever treatment strategies. It is exactly what I find so exhilarating about a juicy electrolyte case in the ICU.

The principle variables in secondary hyperparathyroidism are:

PTH
Phosphorous
Calcium

And I use one additional lab that is generally ignored in the guidelines, alkaline phosphatase.

To bend these numbers we have a variety of tools with interesting effects, mechanisms of action and side-effects. The principle therapeutics:

low phosphorous diet
calcium containing binders
non-calcium binders
calcitriol
paricalcitol and doxercalciferol
cinacalcet

And additional therapeutics that can be brought to bear in difficult cases or in unusual circumstances

dialysate calcium concentration
parathyroidectomy

And K/DOQI provided cleanly laid out treatment goals:

PTH 150-300
Caclium 8.4-9.5
Phosphorous 3.5-5.5
Calcium x phosphorous product < 55

Patients that achieve those targets have a lower mortality risk than patients that miss these targets:

The numbers (0 of 3, 1 of 3, etc) refer to the number of months a patient is at the K/DOQI target in the quarter, PTH was measured only once a quarter

The problem is that no one has performed a prospective randomized controlled trial showing these targets improve outcomes. We want to believe that the retrospective data showing a survival advantage with cinacalcet and paricalcitol are real and that the observational data showing better calcium and phosphorous (and to a smaller degree, PTH) results in better patient outcomes.

Teng et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med (2003) vol. 349 (5) pp. 446-56

Block et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol (2004) vol. 15 (8) pp. 2208-18

But given nephrology's previous relationships with retrospective data (see anemia, Kt/V, and statins, and homocysteine) I can't accept that data. I can't take these treatment goals seriously. I appreciate that the fresh KDIGO guidelines readily admit that the emperor has no clothes and that the best they can recommend is to generally keep the calcium and phosphorous close to normal (evidence level 2D) and the PTH anywhere from 150 to 600 (evidence level 2c) or roughly wherever the hell you want it.

I love this figure from KDIGO, essentially once the PTH rises over 150 it provides no information. PTH > 300 has a positive predictive value of only 65% for high turnover disease. And don't miss the laughably small numbers. We are basing global guidelines off of a study of less than 100 patients. From Barreto and Barreto.

It is shameful that Abbott has not done an RCT with survival as an endpoint on Zemplar or Calcijex. They have had 20+ years to do this. Both of the other players in CKD-MBD have taken a chance at building RCT data to support there products:

Genzyme took a poke with DCOR (RCT of sevelamer versus calcium based binders)
Amgen is in the final countdown of EVOLVE (RCT of sensipar + usual care vs usual care)

Abbott the oldest player is sitting on the sidelines.

The lack of data, the lack of clarity, and the reliance on observational data muddles the issue enough that I don't enjoy taking care of secondary hyperparathyroidism. But recently I had a great case, a situation where treating secondary hyperparathyroidism did more than loaded the dice in my patients favor but actually really made a difference.

I have a young dialysis patient who suffers from a horrific trauma a number of years ago. As a result he has profound chronic pain. Much of the pain is back pain but he also complained of diffuse body aches. Earlier this year his PTHs were consistently over a thousand with some over two thousand.

We added 90 mg of cinacalcet daily and the the PTH plummeted to goal. This was in a patient who had not responded to doxercalciferol 10 mcg three times a week. It was nice to see the PTH come down but what made this case standout was that his body aches melted away. We had been sending him to pain clinics and switching narcotics trying to get his pain tolerable and all of a sudden, done. Pain dramatically improved with a log reduction in PTH.

Sometimes I get so carried away worrying about total mortality that I forget about the direct toxicity of high PTH.

Warhol, Coca-Cola and the iPhone

2011-10-02T23:34:00.002-04:00

What’s great about this country is that America started the tradition where the richest consumers buy essentially the same things as the poorest. You can be watching TV and see Coca-Cola, and you know that the President drinks Coke, Liz Taylor drinks Coke, and just think, you can drink Coke, too. A Coke is a Coke and no amount of money can get you a better Coke than the one the bum on the corner is drinking. All the Cokes are the same and all the Cokes are good. Liz Taylor knows it, the President knows it, the bum knows it, and you know it.

--Andy Warhol

Replace Coke with iPhone and that is what I think is so cool about the pocket computer revolution. No matter how rich or how powerful you are, the best phone you can get is the same one you see high-school kids using.

Intriguing thoughts on pulmonary embolism

2011-10-01T01:29:00.001-04:00

The blog post claims that the data on treating pulmonary embolism is shaky, a randomized study from 1960 with a few handfuls of patients that was terminated early after 6 end-points.

The author then goes on to point out that since our methods of diagnosis are so much more sensitive than they were in the 1960s we should be skeptical of using old treatments for this modern concept of pulmonary embolism.

Read it. What do you think?

Medical school humor

2011-09-29T14:13:00.003-04:00

I am knee deep studying for my internal medicine recertification, so my sense of humor maybe a bit warped, but I found this to be a scream:

How the kidney works, a primer for non-medical folks--updated now with fewer errors

2011-09-19T10:36:00.002-04:00

I recently have joined a Bartter and Gitelman group on Facebook. It is a collection of people from all over the English speaking world, each with a long standing chronic disease and all of them are on an diagnostic island where they have never met another person with the disease and are generally seeing docs who are just as unfamiliar with the disease as they are. A lot of them have questions on how the kidney works so this primer is for them

The Nephron

The functional unit of the kidney is the nephron. A functional unit is not a common term so let's spend a sentence or two talking about what that means. a functional unit is the smallest fraction of a system that still accomplishes all the tasks of the entire system. For example, the functional unit of a muscle is a single muscle cell, a myocyte. A muscle's, sole function is to receive a signal and respond by shrinking. They remain shrunk until the signal ends. A single myocyte can do that. Though a muscle contains thousands of myocytes one can think of it as one giant myocyte without losing much.

On the other end of the spectrum is the heart, the functional unit of a heart is the entire organ, it makes no sense to think about a heart without all four chambers and all the heart valves.

The kidney lies in-between these two extremes, the functional unit of the kidney is the nephron, a complex collection of blood vessels, tubes, nanopumps and filters. Each kidney is composed of a million nephrons but you can understand every function of the kidney and understand just about any type of kidney disease by understanding it's affect on a single nephron. You can think of the kidney as being a single giant nephron and not lose much.

The primary role of the kidney is to keep the extracellular fluid (all the water that lies outside of the cells) in an ideal and balanced state. They manufacture the cellular atmosphere in which our cells live. To do this they:

replace chemicals which are consumed
excrete the variety of foreign substances absorbed by our indiscriminate gastrointestinal tracts
excrete the byproducts of our metabolism (the ashes of our body fires)

The basic procedure that is used is can be thought of like cleaning out a closet, take everything out, then put back what is valuable and throw away the rest.

Here are the parts of the nephron that accomplish this:

The glomerulus
The glomerulus is a colander that filters the blood. The blood cells and proteins of the body play the role of the pasta while the water, salts, and small molecules play the role of the water and flow through the colander into the tubules of the nephron. The primary difference between a colander and the nephron is that the water that passes through the colander is discarded as waste. In the body if you were to waste everything that was filtered you would quickly perish.

The tubules
Following the glomerulus, the filtered water, salts and small molecules enter through the tubules. The primary role of the tubules is to reclaim all that is valuable and secrete additional waste that wasn't filtered by the glomerulus. The end of the tubules is the renal pelvis which acts as the grand central station where the millions of tubules, one for every nephron, coalesce.

The tubules are further divided into functional regions. Here are the basic regions:
Proximal tubule
The proximal tubule does big, dumb, bulk reabsorption. Way too much fluid is filtered by the glomerulus.
over 3 ozs (100 ml) per minute, this means that in 30 minutes all of the water in the blood stream would be filtered and in 7 hours all the water in the body would be gone. Clearly this does not happen and the reason it doesn't happen is that 99% of the filtered water is reabsorbed. This is the focus of the early nephron. Actually a way to look at the nephron is that as you move down the tubule from the glomerulus to the bladder less fluid is recovered and more fine tuning occurs.

The proximal tubule, reabsorbs two-thirds of the date, sodium, potassium and many other substances that are filtered. It recovers all of the amino acids, glucose and other carbohydrates needed for energy and building the body. There is some subtle forms of regulation that occurs in the proximal tubule but most control and fine tuning occurs downstream in other segments of the nephron. Many drugs are secreted in the tubule so it is a key site for cleaning the blood of substances that are found at lower concentrations or escape being filtered by the glomerulus for one reason or another.

Loop of Henle
After the proximal tubule, the nephron takes a strange shape. It stretches down deep into the center of the kidney, like a Texas wildcatter digging a deep well. The loop of Henle is the engine which powers both the dilution of urine and the concentration of urine. The control of what type of urine is made is executed at the last minute but the work that makes that happen occurs in the loop. Concentrating or diluting the urine is how the body conserves or wastes water. When you think of what type evolutionary changes were required for animals to leave the ocean, the ability to conserve water by making concentrated urine must have been one of the critical breakthroughs, concentrated urine can only occur if the loop of Henle is working properly.

A lot of sodium, and magnesium reabsorption occurs here. The common water pill furosemide (Lasix) acts on the loop of Henle. The defects in Bartter syndrome are here and act by limiting the reabsorption of sodium, chloride and potassium.

The other important aspect of the loop of Henle is that at the very tip of the loop, the deepest part of the well, the tissue fundamentally changes so that water can not flow through the cells. From this point to the toilet the tissues lining the tubules are impermeable to water, a characteristic found no where else in the body. The collecting tubules can allow water pass through its walls but only under strict control with the use of specific water channels.

Distal convoluted tubule
There is not much to understand about the distal convoluted tubule. It is the site where thiazide diuretics act and is where the mutations that cause Gitelman syndrome is expressed.

Collecting duct
The last segment of the tubules is called the collecting duct and it has three primary roles:

excrete excess acid
excrete dietary potassium
regulate the excretion of water

The potassium situation is unique and is handled unlike other electrolytes. A lot of potassium is filtered by the glomerulus, but that potassium is reabsorbed in the proximal tubule and loop of Henle. By the time the tubular fluid winds around to the collecting tubule, all of the filtered potassium has been reabsorbed. All of the potassium that is excreted by the kidney must be secreted by collecting tubule. As far as potassium is concerned the only part of the nephron that matters is the collecting tubule.

The big finish
After the collecting tubule there is the renal pelvis where all of the collecting tubules empty into a common chamber and then flows into the ureters, the long tubes that drain the kidney into the bladder where it is stored until voiding. After urine leaves the tubules it does not undergo any further chemical changes.

The perfect organ
The last bit that is important is the concept of balance. One of the perfect things about the kidney is that it keeps the body in balance. In patients that are not growing, all of the sodium that is consumed is excreted by the kidney. When I want to investigate whether a patient's blood pressure might be due to excessive salt in the diet, I do not try to get the patients to remember and report what they eat, I simply have them collect all of their urine for 24-hours and measure the amount of sodium in the urine. If they have 3 grams of sodium in the urine, then they are eating 3 grams of sodium. This can be done with any substance that is ingested and then excreted unchanged by the body. Examples of intake that can be assessed with a 24-hour urine collection include:

potassium
sodium
phosphorous
water
protein

- Posted using BlogPress from my iPad
- hat tip to Steve Rankin for fact checking

Reminder of a great case from the archives

2011-09-19T08:45:00.002-04:00

Last year I had one of the most severe cases of hyponatremia I had ever seen. Last night I was flipping through iPhoto (looking for the drawings Margret Atwood did of my alter ego, Kidney Boy) and found this photo...

Just looking at the labs gives me chills. Here is the whole story.

Michelle Bachmann taking up the anti-vaccine crusade

2011-09-16T14:35:00.002-04:00

Earlier this week Congressperson Bachmann took a crack at the HPV vaccine, saying that she heard from some person that her daughter had become a retard after getting vaccinated.

"There’s a woman who came up crying to me tonight after the debate," Bachmann said after the debate, where she had told Perry on stage that she was "offended" by his decision. "She said her daughter was given that vaccine. She told me her daughter suffered mental retardation as a result of that vaccine." The Telegraph

It's unfortunate that people who don't die of cervical cancer never realize it and unable to talk with presidential hopefuls. I dream of day when nephrology fellows won't get calls in the middle of the night to handle potassiums of 8 caused by cervical cancer associated bladder outlet obstruction.

Interesting infographic on the HPV vaccine and cervical cancer. Click here for a readable version.

Outpatient hyponatremia

2011-09-16T13:54:00.000-04:00

Almost all of the hyponatremia I see is inpatient, but this week a woman was referred to my clinic with a sodium of 128. She has a sharp family doctor who ordered all the right tests. Here are the key pieces:

Plasma sodium 128
Plasma osmolality 277
Urine osmolality 180
Urine SpGrav 1.005
Urine sodium 14

She has a history of hypothyroidism but her TSH was over suppressed, no hint of hypothyroidism. She was not taking any diuretics. She was on an SSRI that could cause SIADH but the low urine osmolality and low specific gravity argue against excessive ADH activity.

The case hinges on the low urine osmolality. This is a rare case of ADH-independent hyponatremia. All of the major causes of hyponatremia (volume depletion, diuretics*, heart failure, SIADH, etc) are driven by ADH which prevents the kidney from clearing free water. The low urine osmolality indicates the kidney is not under the influence of ADH and doing what it needs to in order to correct the sodium, i.e. excreting excess water in the form of dilute urine.

I believe there are only a few causes of ADH-independent hyponatremia, and only two occur with any regularity:

Psychogenic polydipsia
Tea and toast syndrome
Reset osmostat (rare)

When the kidney is making dilute urine and the patient has hyponatremia the problem is not in the quality of the urine, which is appropriate, but in the quantity of urine, which is inadequate.

She described her diet as a peanut butter and jelly sandwich for breakfast, some fruit and juice with some nuts for lunch and nothing for dinner. Her fluid intake was high (4-5 cups of coffee, a large water bottle of water, some juice, some soda, and a couple of additional glasses of water) but no where near enough for psychogenic polydipsia.

I suspect she has tea and toast syndrome. I am checking a 24-hour urine osmolality to gauge her daily osmolar load and then plan to have her increase the amount of protein and minerals in her diet while trying to taper her fluid intake.

New kid on the block: The Kidney Doctor

2011-09-14T15:42:00.000-04:00

I first met Ajay Singh when he came to St John Hospital as part of a symposium on chronic kidney disease in 2004 or 2005. It was a great meeting and Singh gave two memorable lectures.

The first was a dismantling of the MDRD equation as an accurate measure of GFR. He was speaking against an equation that was way better than a simple creatinine but had some real problems, especially when used in patients without kidney disease. It was a inflammatory and a bit wonky for a conference directed to primary care doctors. Here we, the local nephrologists, were trying to get our doctors to recognize occult CKD by abandoning serum creatinine in favor of the superior eGFR and then the invited expert comes in and tells them how stupid this is.

His second lecture was the correction of anemia dog-and-pony show. He gave an amazing and persuasive presentation in favor of correcting of anemia in renal disease. Though the data was all retrospective and observational it was clear that Dr. Singh was personally a few steps past equipoise. At the time CHOIR was in full swing recruiting and retaining patients and my group was part of that process as a research site for CHOIR.

Five or so years later he returned to talk with our fellows and staff regarding anemia. This was after the publication of CHOIR, but I believe before the release of TREAT, though my memory is a bit hazy on the timing.

What I do remember is that he talked about the dangers of correcting anemia and the lack of data supporting its use. I remember being so angry. I felt that for the last half dozen years I had worked to convince my CKD patients that they needed to enroll in our anemia clinic, needed to come to our office for EPO shots and iron infusions, and that all this would make them feel better, protect their heart and prolong their life, all purported advantages of ESA therapy. And now Mr. Harvard returns and tells us that this is wrong, without ever apologizing, without even mentioning how he'd jumped the fence.

I stopped him mid-lecture and told him that the last time he'd been in Detroit he'd been telling us how important it was to treat anemia and now he had completely changed positions. Dr. Singh paused, looked at me, and gave the best answer possible. I can't remember his exact words, so I'm paraphrasing here,

"The data has changed. Now we know more and what I'm telling you is what is currently correct. In medicine, there is no room for intellectual loyalty. We must be loyal to our patients not our theories. The reason my position has changed is that I am following the data. Would you want me to do anything else?"

His answer completly satisfied me and it extuinguished my rage. I was better able to deal with my regret and embarrassment at having to abandon a long held belief and practice pattern at the feet of new data.

His new blog is off to a flying start with a productivity that hasn't been seen since Nate Hellman and quality that, to my eyes, no one can match.

Thanks Ajay, I'm looking forward to following your blog.

HIPAA violations go mass production

2011-09-10T01:00:00.001-04:00

Stanford let demographic information on 20,000 ER visits escape onto the web.

A billing contractor created a spreadsheet containing names, account numbers, diagnosis, and length of stay for every admission to the ER for 6 months. Somehow, this spreadsheet was uploaded as an attachment to a post asking for help making bar-charts (you can't make this up) to the tutoring website Student of Fortune. The information remained on the site freely available from September 2010 to August 2011.

Get all the details at the New York Times.

Maybe the next time we get alarmed about the threat to privacy from a case report or educational lecture we should think about the losers that are releasing medical data by the bucketful.

Free e-book: Oh Doctor, The Places You Will Go...

2011-09-08T16:37:00.000-04:00

Dr. James Chang of the personal finance blog, PoorMD, has written a parody of Dr Seuss' classic Oh, the Places You'll Go! It is a candid look at the journey people make in order to become doctors. I found it charming. Go download it. All of the illustrations were done on his iPad. Terrific.

Great image from wikipedia

2011-09-06T23:30:00.000-04:00

This graph from wikipedia allows you to see how different substances concentration in blood varies. Who new that the lowest molar concentration of all was PTH?

Hyperkalemia or not

2011-09-05T23:25:00.000-04:00

A patient came to the hospital with a swollen arm. The ED suspected a DVT and ordered a doppler ultrasound which confirmed their suspicion. The admission labs included a chem-7 which revealed a potassium of 7. Her creatinine was 1 and she wasn't taking an ACEi, ARB, aldactone, ketoconazole, or potassium supplements. The ER was surprised and repeated the study and checked an EKG:

Narrow QRS and unimpressive T-waves

The EKG gave no hint of hyperkalemia, though EKG changes are not a sensitive marker for hyperkalemia. The ED gave insulin, glucose and Kayexalate for the lab finding of hyperkalemia. We were consulted to determine the cause of the hyperkalemia. The patient's past medical history was significant for primary thrombocytosis and during the hospital stay her platelet count rose to over a million.

dats a lot o'platelets

We presumed that his hyperkalemia was actually pseudohyperkalemia due to the high platelet count. Platelets release potassium when they clot and the risk of pseudohyperkalemia rises as the platelet count approaches a million.

You remember this classic NEJM article from 1962.

We then sent the patients blood to the ABG lab in a heparinized syringe rather than a red top and the potassium normalized. Platelets release potassium when they are activated. By measuring the potassium in whole blood rather than serum, the contribution of platelet activation is prevented. The ABG results are the electrolytes to the far left in the screen-grab below (click to enlarge).

- Posted using BlogPress from my iPad

Great animated gifs from Dr. Strangelove

2011-09-04T23:06:00.001-04:00

General 'Buck' Turgidson listening to Premier Kissoff

Mr. President, we are rapidly approaching a moment of truth both for ourselves as human beings and for the life of our nation. Now, truth is not always a pleasant thing. But it is necessary now to make a choice, to choose between two admittedly regrettable, but nevertheless distinguishable, postwar environments: one where you got twenty million people killed, and the other where you got a hundred and fifty million people killed.

Peter Seller's best movie?

From If We Don't Remember Me.

Hypertensive emergency with thrombotic microangiopathy

2011-08-31T14:13:00.000-04:00

We admitted a patient with a rip-roaring hypertensive emergency and microangiopathic hemolytic anemia (MAHA). On admission his creatinine was 4. The creatinine kept creeping up despite controlling the blood pressure. Additionally his LDH, platelets and schistocytes either normalized or were heading towards normal, yet the creatinine continued to rise. Early on in his hospitalization we started spironolactone with minimal effect on his blood pressure and no improvement in renal function. As the patient spiraled toward dialysis we decided to attempt to block aldosterone secretion responsible for the thrombotic microangiopathy. We started captopril 50 mg tid. I planned to titrate it up to scleroderma renal crisis-like doses.

Murphy must have been working the night shift because the following morning he was complaining of a swollen lip. We stopped the ACEi due to angioedema. We started aliskiren instead. She tolerated that and for the first time in a week her creatinine leveled off and started to come down.

The biopsy is pending.

Was his renal function about to turn around anyways? Who knows?

The team was conflicted on starting the ACEi. So many times we try to minimize exposure to ACEi in acute kidney injury to maximum glomerular perfusion. He was admitted with severe hypokalemia so aldosterone and renin levels were drawn on admission. Those are send-out labs at our institution and we didn't get results until into the second week. Aldo 60, plasma renin activity 5. That's among the highest aldo I have ever seen.

There is experimental evidence pointing to aldosterone having direct vasculopathic activity driving microangiopathic hemolytic anemia.

Chander et al, took 28 Stroke-prone spontaneously hypertensive rats and then divided them into four groups:

Sham surgery
Bilateral adrenalectomy
Bilateral adrenalectomy + angiotensin 2
Bilateral adrenalectomy + aldosterone

Dexamethasone was provided to adrenalectomy rats to prevent Addison's disease.

Blood pressure was elevated in all rats but was less severe in the adrenalectomy group.

Proteinuria was worse in the control group and when aldosterone was restored.

The experimental conditions resulted in malignant hypertension with MAHA as seen in the pathology from the control animals (panel A). Adrenalectomy resulted in sparing of the renal architecture (panel B) and the addition of angiotensin did not induce MAHA (panel C). The addition of aldosterone did induce similar pathology as seen in the control animals implicating aldosterone as the bad actor in this animal model of malignant hypertension and MAHA.

MAHA is seen in panel A, control animals
Adrenalectomy (panel B) prevents the characteristic lesions of malignant hypertension
Likewise with adrenalectomy + AT2 (panel C)
The fibrinoid necrosis returns with the aldo infusion in panel D.

From Chander's data it looks like aldosterone is the bad actor, I was unable to find information on using spironolactone to reverse MAHA. There is data showing a protective effect of ramipril to prevent MAHA, again using an animal model of malignant hypertension.

I look forward to see how much renal recovery he gets with aliskiren, though it will be impossible to prove that it was aliskiren, I for one believe.

Another point we debated was the use of aliskiren after ACEi induced angioedema. We decided to use it. Here is what the package insert has to say:

Angioedema: Two cases of angioedema with respiratory symptoms were reported with Tekturna use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with Tekturna use including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with Tekturna compared with 0.5% with placebo. In a long term active control study with Tekturna and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms [see Warnings and Precautions (5.2)].

++++++++

Below is an annotated biography of additional information, mainly focussing on the poor renal outcomes associated with MAHA in malignant hypertension.

JNCVII defines hypertensive emergencies as:

Hypertensive emergencies are characterized by severe elevations in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction... Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute MI, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, or eclampsia.

Strange that acute renal failure is not mentioned as a complication. The recommendation is to reduce the blood pressure by no more than 25% in the first minutes to an hour and subsequently shoot for 160/100 for the next 2-6 hours. The authors point to 2 exceptions: aortic dissection where the SBP should be less than 100 and in acute stroke where the data is less clear. (a moment of clairvoyance for the JNCVII crew as they correctly predicted the lack of benefit from aggressive blood pressure control in the midst of an acute stroke. This was confirmed with 2011's SCAST study)

Meta-analysis showing the lack of benefit from blood pressure treatment in acute stroke

IV blood pressure agents helpful in hypertensive emergency from JNCVII

The first article we looked at was Bert Jan van den Born's retrospective review. These authors looked at patients with malignant hypertension. Cases were identified by looking at every hospital admission with the diagnosis of hypertension and then screening the charts for an ophthmology exam showing:

bilateral flame-shaped retinal hemorrhages
bilateral linear "splinter" retinal hemorrhages
or "cotton-wool" exudates.

Wonderful pic of cotton-wool exudates and splinter hemorrhages. Thanks ACP

Flame hemorrhages. Without permission from AAO

If I had to wait for an ophtho consult to make a diagnosis, half my patients would be ready for discharge with the diagnosis still pending.

After patients were deemed to have hypertensive urgency, they were categorized as having MAHA. This was defined as a low platelet count with either an elevated LDH or schistocytes. Additionally the LDH/schistocytes and the platelets had to recover following recovery from the hypertensive crisis.

The endpoints were creatinine and proteinuria at admission and follow-up creatinine.

The study found 110 patients that met the criteria, and 97 were ultimately available for analysis.

4 were excluded because the retinal changes were due to intracranial masses rather than hypertension.
5 were excluded because of a lack of platelet count
4 were excluded because they had an alternative explanation for thrombocytopenia

26 of the patients had MAHA. The MAHA cohort was more:

black (73 vs 35%)
hypertensive (242/150 vs 225/145
uremic (Cr 7.8 vs 1.4)
proteinuric (88% vs 41%)

To convert creatinine from micromol to mg/dl, divide by 88

Dialysis was needed in 15 of the 26 patients with MAHA and 2 of the 71 without MAHA. They had renal recovery in 6 of the dialysis patients: four within 2 months, one at 8 months and the last at two years!

Then the authors drop what might be the worst line of logic ever published in Hypertension:

Improvement of renal function, defined as a reduction of serum creatinine >50% compared with baseline, was noted in 17 patients during follow-up. Cox regression analysis showed that MAHA and systolic blood pressure at admission were the most powerful indicators of renal improvement with an HR of 0.24 (95% CI, 0.08 to 0.75) and 1.02 per mm Hg increase in systolic blood pressure (95% CI, 1.01 to 1.05; Table 4). Improvement of kidney function over time in patients with and without MAHA is shown in Figure 4.

The authors try to make the case that there is more renal healing with MAHA than in the absense of MAHA without specifically addressing that the patients with MAHA had 20x the rate of dialysis of those without it or that the average Cr of MAHA-absent patients was only 1.4, making a 50% reduction in serum creatinine require the growth of a third kidney. Ridiculous.

The second article was Gonzalez's study on the long term renal outcome following hypertensive emergency. The introduction begins with a nice history of hypertensive urgency. They state that patient survival was very poor before the 1970 and the development of effective anti-hypertensive drugs. After 1970 renal and patient survival climber to 50 and 75% respectively at five years. A decade later, with the introduction of calcium channel blockers and ACEi in 1980, survival rose to 81% renal and 90% patient survival at 5 years.

Gonzalez retrospectively looked at patients with a diagnosis of malignant hypertension. They also required retinal changes (hypertensive retinopathy grade 3 or 4). Strangely, they excluded a third of patients who had secondary hypertension behind the malignant hypertension. This, along with a few other exclusions due to lack of follow-up for various reasons, left 197 in the cohort. The cohort was divided by ultimate renal outcome. Group 1 had stable or improved renal function while group 2 had worsening renal function.

They found that patients who developed worsenning kidney function had at baseline:

pre-existing CKD
higher creatinine on presentation
more proteinuria
more microscopic hematuria.

125 (85%) had acute kidney injury on admission and 15 required dialysis. 8 of these had no prior CKD. Only 2 patients recovered sufficient renal function to stop dialysis.

On multivariate analysis only proteinuria in follow-up was associate with a lack of renal stabilization or improvement.

83% of the patients with worsening kidney function (group 2) ultimately were started on dialysis. Remember, they had over 30 years of follow-up for some of these patients and there is some selection bias as group 2 was defined by a lack creatinine stabilization/improvement.

Since the cohort was collected over 30 years (1974-2007) the authors made some observations regarding the change in malignant hypertension over time. There was no change in the incidence, however there were fewer people needing dialysis. Treatment evolved from diuretics to calcium-channel blockers and RAS blocked.

The third article was a case report and lit review by Shavit et al. The article defines malignant nephrosclerosis as renal failure due to malignant hypertension. They describe three cases with varying outcomes:

55 year old admitted with a blood pressure of 220/130, Cr 11, normal platelet count, LDH 1,100. A renal biopsy showed concentric intimal hyperplasia, fibrinoid necrosis of arteriolar wall, shrinkage of the glomerular tufts. The patient remained dialysis dependent 2 years after presentation.
55 year old admitted with 240/125, Cr 13, LDH 1,430, normal platelet count. Kidney biopsy revealed intimal thickening, luminal narrowing, fibrinoid necrosis. His creatinine improved over 2 months and he remained dialysis free with significant CKD 2 years after presentation.
28 year old admitted with a blood pressure of 210/135, Cr 4.5, K 2.9, normal platelet count. Kidney biopsy showed severe intimal thickening, and fibrinoid necrosis. Creatinine improved over 2 weeks to 1.8 and remains stable at 3 years of follow-up.

The authors then review the literature with an interesting discussion that renin and aldo levels are commonly elevated in malignant nephrosclerosis and that there is a strong correlation between renin activity and the presence of MAHA, suggestive of renin mediated vascular damage.

They mention research finding low levels of ADAMTS13 in malignant hypertension. ADAMTS13 level fall as LDH levels rise and platelet count fall. A follow-up study of 21 patients failed to confirm these findings.

The next article we pulled was by Akimoto et al, Clinical Features of Malignant Hypertension with Thrombotic Microangiopathy. This was retrospective review of 16 cases of malignant hypertension. MH was defined as an elevated blood pressure with retinal changes. MAHA was defined by an increase in LDH, low hemoglobin and low haptoglobin. Additionally to meet the definition of MAHA patients needed to normalize these indices after correction of the blood pressure. Of note 7 patients had biopsies. Five of those biopsies showed evidence of malignant nephrosclerosis (fibrinoid necrosis) but only 3 of them met the authors' clinical definition of MAHA. Interesting that those reasonable clues could be missing 40% of cases.

They found higher aldosterone levels in patients with MAHA than in patients without. They found a tight correlation between aldosterone levels and LDH, R² of 0.4 (p=0.0096).

Four of the seven patients with MAHA required dialysis, however 2 were able to come off. Three of the nine patients without MAHA required dialysis and none recovered renal function.

cyberNephrology, what a piece of cyberCrap--updated

2011-08-29T09:19:00.002-04:00

I was browsing the Renal Fellow Network and saw a link to a website I hadn't previously heard of, cyberNephrology. It had a prominent position on the list of Other Nephrology-Related Blogs, so I went to check it out. The prefix cyberis very 1990's and cyberNephrology does not disappoint it. It has that a few years after the zombie apocalypse feel.

Starting at the top the What's New page links to a pair of talks from 2009.

The three large banners are role overs that open to text based pages. The communication page is essentially a link to an E-mail discussion group. In today's world of Twitter and Facebook are e-mail discussion groups relevant? Hint: No.

According to cyberNephrology, e-mail discussion groups are not only a relevant form of communication, they are the only forms of communication.

The additional resources includes a link to the Highlights of the Nephrol e-mail discussion list, last updated in 2000. A link to a Nephrology Internet Bibliography, last updated in 2002.

The nephrology related websites is a page of links to a couple of dozen large institutions and a handful of defunct links to smaller sites, The Catalan Transplant Foundation (now a squatters site) KidneyWeb (a site that brings back memories of the worst of GeoCities), e-dialysis.org (now behind a paywall). Amazingly this page claims it was updated in January 2011, though they don't show any link-love back to the Renal Fellow Network.

The Education link on the home page leads to a page that is similarly outdated with links to NKF's spring meetings up through 2008. The funniest part is that 2008 is considered next years meeting, as there is a separate link to Past meetings.

The other trip down memory lane is the link to "New Technology--Palm OS, PDA." Unfortunately, for nostalgia's sake, the link is broken.

The last target on the home page is a new vision. This leads to more gobbley gook but does place the responsibility for this load of crap at the feet of none other than PBFluids hero, Dr. Robert Schrier. Shame on you Dr. Schrier.

The new vision page includes a contact form. I sent a comment and after pressing send I was redirected to this page of crap.

What's the chance I ever hear word one from them?

There was a time when having a "homepage" counted for something, but now these are just embarrassing relics. NKF should just euthanize cyberNephrology.

It also calls into question what type of editorial control RFN has after getting endorsed by NKF. Do the editors really feel that cyberNephrology is a worthy site that belongs on the same list as Clinical Cases-Nephrology and Dialysis from the Sharp End of the Needle? Or was cybernephrology added in deference to their new overlords?

Update 9/1/11:

About 16 hours after posting Dr. Kim Solez commented here. You can read his plans for cyberNephrology below, but part of his plans included shuttering cyberNephrology and starting a new google+ charged version of the Nephrol e-mail list serve. Additionally a number of readers have chimed in, through the comments and other communications, regarding the value of the Nephrol list serves. This maybe a case where this author judged a book by its cover.

That said Dr. Solez has not made good on his promise and cyberNephrology is still up, though I occasionally get pointed to the new NephrolPlus project (not sure what's up with that). When cyberNephrology ultimately disappears you maybe able to dig up the bones at the NKF's kidney.org site, which currently carries a partial copy of cybernephrology.

Lastly, the Renal Fellow Network has removed cyberNephrology from their website and have, to my satisfaction, established that there is no editorial control from the NKF. I feel a little foolish for pointing that finger. Sorry guys.

Should Registered Organ Donors Get Priority as Recipients?

2011-08-25T14:23:00.000-04:00

Pay to Play: Should Registered Organ Donors Get Priority as Recipients?

Could fixing (or more realistically improving) organ allocation be this easy?

Good luck Steve and thanks for your dent in the Universe

2011-08-25T01:17:00.002-04:00

We're here to make a dent in the universe. Otherwise, why even be here? We're creating a completely new consciousness, like an artist or a poet. That’s how you have to think of this. We're rewriting the history of human thought with what we're doing. --Steve Jobs

I was sad to hear the news of Job's resignation from Apple. My wife and I watched Pirates of Silicon Valley as a toast to the man who I view as a modern Leonardo De Vinci. A genius who revolutionized our world.

I said hi to Steve once. On the day the Fifth Avenue Store opened in New York I was walking around the plaza and saw Steve walking up to the store with another person. I was about ten feet away and I said, "Steve!"

He turned to me and I said, "You changed my life."

He smiled, said thank-you and then kept walking.

I felt like such a dork. "you changed my life." Ughh. I wish I had said something better.

It was 2006 and all I had with me was a Palm Treo

Later that night, my wife and I saw a show (I think it was Avenue Q) and then went to check out the scene at the Cube. We waited in line and went down into the store on opening night. It's the only Apple event I've witnessed.

Still smiling after saying hi to Steve hours
earlier, and my extremely understanding wife

The resignation letter states that he will continue to have a role at Apple, and it's likely we will see little different from Apple but as I wrote when he took his most recent leave of absence, "I want to live in a world where the man who launched the PC revolution is still leading it." As of today, that's no longer the case.

So long Steve, and thanks for your dent in the universe.

Crazy idea or genius? Nephrology Merit Badges

2011-08-24T08:49:00.002-04:00

I want to create a series of buttons to give to residents and students to mark achievements in nephrology.

My birthday is coming up, looking at the 1 inch beginner button system

One of the common resident complaints regarding nephrology is that it's too hard. The nephrologist response to this complaint is usually to deny the difficulty, because its not hard for the nephrologist. Perhaps that denial is counterproductive, first it's hard to disrupt a widely held belief that is continually reinforced by the community of medicine, secondly when you deny the difficulty you insult the intelligence of the student struggling with new concepts. Its essentially saying, "Hard? differentiating among the pulmonary renal syndromes is easy, what are you stupid?"

Instead of denying the difficulty we should re-frame the meme. Yes, nephrology is hard and look how cool it is that you mastered these concepts.

Merit badges, or pieces of flare as my fellow interjected, would add levity and encourage residents to tackle deeper concepts.

Potential nephrology merit badges:

It's the heart, no it's the kidney, no it's the heart, no it's the kidney...: diagnose and successfully treat a case of cardiorenal syndrome
ABG guru: interpret ABGs showing all four primary acid-base disturbances
Quinton: insert a temporary dialysis access to provide emergency dialysis access
Tissue is the Issue: perform a renal biopsy
Look Closely: correctly interpret a urine microscopy specimen
K/DOQI Genius : use the K/DOQI guidelines to craft a plan of care for a CKD patient
RIFLEry: use the rifle criteria to correctly stage a case of AKI
RTA (pronounced like Fonzie would RTAAAAAA!): use urinary anion gap and other clues to correctly diagnose and classify an RTA
Bud Rose: use free water clearance to draw meaningful conclusions about hypo- or hypernatremia
Put on your Helmut (Rennke): be a star in the pathology room
Gerry Appel: exceptional management of nephrotic syndrome
Ron Falk: diagnose and manage a patient with ANCA-associated vasculitis
The Town Schrier: Use FENa, FEUrea and BUN:Cr ratio in a meaningful way to diagnose a subtle case of pre-renal azotemia
Mark Halperin: Master of the Cortical Collecting Duct: use the TTKG equation intelligently to help in the management of a patient
Wisdom of Solomon: prevent a case of contrast nephropathy
Cry me a river: for expertise in the use of high dose diuretics
EPA Super Fund Site: use dialysis to correct uremia in AKI

Suggested merit badges from other creative nephrologists:

Way to Go KDIGO: use the KDIGO guidelines to do what ever you want to your dialysis patient
Golden Pocket: Forgetting to tighten the cap on the urine that you are bringing back to the lab to spin

Thanks to Steve Rankin and Edgar Lerma

The "are you a medical nerd?" quiz

2011-08-21T23:29:00.001-04:00

Another great post from Cartoon Guide to Becoming a Doctor

Follow the link to interpret your score

As I finished up this post I noticed that I had previously created the tag "Nerd Humor." Having a nephrology blog with that tag should be worth 5 points, minimum.

Antibiotic Locks

2011-08-21T11:27:00.000-04:00

I'm finding my self using antiniotic locks more and more. Michael Allon, one of the key investigators who drove the adoption of albuterol for hyperkalemia is a player in this space. Here is one of his convincing studies:

Treatment of catheter-related bacteraemia with an antibiotic lock protocol: effect of bacterial pathogen

Calling all nephrologists! If you care about anemia, you have until August 30th

2011-08-20T18:38:00.006-04:00

The Centers for Medicare and Medicaid Services has proposed changes in the Quality Incentive Program (QIP) for 2013. The changes specifically involve anemia. The QIP was created to assure that even though the costs of providing dialysis care are born exclusively by the dialysis provider, there are specific quality goals that if not met result in financial penalties. The quality goals currently place are:

Percentage of Medicare patients with an average Hemoglobin < 10.0g/dL (Hemoglobin Less Than 10g/dL Measure)

Percentage of Medicare patients with an average Hemoglobin > 12.0g/dL (Hemoglobin Greater Than 12g/dL Measure)

Percentage of Medicare patients with an average Urea Reduction Ratio (URR) ≥ 65 percent (URR Hemodialysis Adequacy Measure).

Dialysis units that fail to hit the goals perscribed by the quality score receive a reduction in the Medicare payment by 0.5-2%. It should be apparent that the required hemoglobin targets ares problematic, especially given the recent action by the FDA (see my recent post Between a rock and a hard place). CMS is proposing the elimination of the floor on hemoglobin targets:

...Therefore, for the PY 2013 ESRD QIP, we propose to continue to use the following two measures previously adopted for the PY 2012 ESRD QIP:
Hemoglobin Greater Than 12g/dL Measure.

URR Hemodialysis Adequacy Measure.

This feels wrong to me. Creating an economic incentive that puts the cost of treating anemia on the provider but doesn't provide any minimal goals may result in a race to the lowest hemoglobin. What's to stop a rogue dialysis unit from removing ESAs from their formulary. We can all freely admit that ESAs have some previously under appreciated risks and that our enthusiasm for treating anemia was not entirely evidence-based, but our response to should not be to turn back the calendar to 1988.

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter represents a 98% reduction in transfusions. Revolutionary. And this doesn't even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

CMS states that they cannot add another unique quality indicator for 2013 and are looking toward 2014 to do this. In the absence of new quality guidelines they should keep the goal to maintain a hemoglobin over 10 g/dl but lower the target to 9 g/dL for 2013.

Patients deserve an incentive that keeps providers conscious of anemia. In study after study, low hemoglobins walk hand in hand with poor outcomes. The concern regarding anemia has been driven by attempts to normalize hemoglobin. It is clear that normalization is hazardous and without scientific support; however a failure of the experimental group does not mean we should abandon the therapy given to the control group. In every study the control group received ESA to maintain hemoglobins at least 9 g/dL. Removing the hemoglobin floor from the quality measures would be giving a de facto license to withhold an important medication from dialysis patients.

The TREAT trial is the best study every done on outcomes in CKD with an ESA.

These dosing groups resulted in an effective separation in hgb with little profound anemia

I have copied this post to Regulations.gov as my comment on the latest guidelines.

The deadline for comments is August 30th.

A science liaison at Amgen told me that Amgen was advocating for a hemoglobin floor of 10 g/dl. The Renal Physician Association is also supporting a hemoglobin of 10 g/dL. [This paragraph was updated 8/22/11, after a complaint that I mis-interpreted Amgen's position. My apologies.]

I have heard that CMS has received few comments from physicians. Embarrassing. Anemia is important and nephrologists should care how the governments crafts incentives that will change how our patients are treated. Go now and comment. Tell CMS what you think.

If you are still looking for a reason to read Presentation Zen...

2011-08-19T14:54:00.000-04:00

Presentation Zen has an excellent post on the use of faces in slides. Great stuff.

Medical Education in One Panel

2011-08-07T15:02:00.001-04:00

Not sure where the original came from but I found it here, via @FutureDocs

Great article on the Nesiritide debacle

2011-07-29T13:26:00.001-04:00

There has been some great articles regarding the expensive, waste of a decade induced by nesiritide.

I like this article the most because it's written by someone who is not in medicine. It tackles many of the same issues I looked at in my post, The problems with numbers, namely when drugs are approved based on intermediate end-points bad things can happen.

The best thing we can say about niseritide is that when the definitive trial was finally done, the previous concerns about renal failure, were shown to be merely illusions created by the smoke and mirrors of meta-analysis.

Acute renal failure was an early concern regarding Nesiritide...

...but when the right placebo controlled trial was done, no renal failure.

So go and read Carolyn Thomas' view of nesiritide and see how we have failed the people we are entrusted to care for.

The Onion takes a shot at Powerpoint

2011-07-28T16:33:00.000-04:00

Well done

Davita: is the vial half empty or half full

2011-07-27T13:22:00.000-04:00

Early Tuesday, I caught half a headline about drugs being wasted at the expense of Medicare and to the benefit of some dialysis company. A few hours later I saw the first caustic tweets:

Just some of the angry tweets

Then I started getting direct messages asking for my thoughts. Recently, Davita has been getting more than its share of bad press recently and this seemed like more of the same. The facts of the news story, as far as I can tell, are as follows

A former medical director and nurse brought a whistle blower suit against Davita
They accuse Davita of using large vials to administer IV drugs during dialysis. The large vials resulted in excess medication being wasted
Medicare pays for the entire vial regardless of how much is wasted
The Justice department investigated this claim for more than two years and decided not to join the lawsuit

My first reaction was Davita had done a bad, bad deed here but the more I thought about it, the more that seemed to be a rush to judgment. The fact that the Justice Department, after investigating for two years, did not join the lawsuit became the itch I could not ignore. My interpretation, is that the Feds looked into how Davita was handling the drugs and they did not find any unlawful activity.

So I was satisfied with the assumption that the way Davita was handling the drugs was legal. However, even when things are within the letter of the law we want our medical institutions to use resources efficiently. Clearly, intensionally pouring drugs down the biohazard drain, as the whistle blowers contend, is not the most efficient use of medical resources. The problem was the Medicare reimbursement system. For years, Medicare underpaid for the dialysis procedure so that dialysis providers had to turn themselves into high-end retail pharmacies that peddled Epo, and Zemplar in order to keep the lights on. With this type of system the providers were incentivized to use as much drug as possible. This perversion of fee-for-service has been at the root of almost all of the recent scandals in dialysis units. The recent anemia controversies were driven to the forefront largely because dialysis companies were payed for giving drugs not for patient oriented outcomes.

Its clear to me that retail pharmacy system was not the system we wanted. The laws need to change and you know what? This system is no longer the law. Bundling began earlier this year and removes these perverted incentives in order to better align provider and patient goals. In response to the new incentives you know what happened? The vials became right sized and Epo use plummeted. It's too early to see how bundling effects patient outcomes but Davita and the other Large Dialysis Organizations are responding to the new incentives.

The lesson here is that incentives drive medical decision making. Incentives need to be implemented thoughtfully because small, seemingly minor holes can be blown wide open and introduce major distortions in the delivery of care. In terms of this whistle blower case, I think we shouldn't dwell on the cows leaving the old barn that has been replaced by one with automatic and secure doors. The old reimbursement system was broken and has been fixed (or at least changed) and I don't think there is much to be gained by dwelling on the previous system's inefficiencies and errors.

So as I see it:

Davita administered and wasted dialysis drugs in a way that is uncomfortable, and inefficient but legal.
The Government realized the incentives were not aligned with better outcomes and changed the incentives
Davita and the other large dialysis organizations have changed their purchasing and administration procedures in response to the new incentives
A couple of former employees want to sue Davita for its legal, but opportunistic, drug handling behavior under the old incentives

Transparency: I am a part owner of a dialysis joint venture with Davita and one of my partners, Robert Provenzano, is Davita's VP of Medical Affairs.

Safari's Reader function in Lion

2011-07-25T22:23:00.000-04:00

I upgraded to Lion on my MacBook Air last week and I'm using Safari in full screen mode. One of the side-effects of this is that many text based sites are too wide for comfortable reading.

Clicking "Reader" in the address bar (or command-shift-R) drops a shadow across the page and opens an overlay containing the core text of the page minus annoying ads and other visual distractions. Really nice.

Click here

and see this uncluttered clean version of the text

The reader feature was introduced with Safari 5 as part of Snow Leopard but it wasn't until I started living in full-screen mode that the utility of this feature presented itself.

The problem with numbers, the curse of intermediate end-points

2011-07-23T02:06:00.002-04:00

The curse of treating chronic kidney disease is that one is always treating patients to the numbers:

Blood pressure. I need to get my patients below 130/80
Cholesterol. I need to get their LDL below 100
Metabolic bone disease. I need to keep their PTH

KDOQI

Stage 3: 35-70
Stage 4: 70-110
Stage 5: 150-300

KDIGO

In patients with CKD stages 3–5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (hey KDIGO, thanks for the guideline)

Diabetes. I need to keep their Hgb A1c less than 7
Anemia. I need to keep their hemoglobin

Either 11-12
or less than 12 (see prior post)
or high enough to prevent transfusions (Nephrology, clear as mud)

But these numbers are all intermediate, and from a patient perspective, pretty abstract. Patients don't get PTH angina. Targetting the numbers is a way to shift the odds toward better patient outcomes, to load the dice in the patient's favor. However we cannot allow the numbers to substitute for the real goals of care. I don't really care about your blood pressure, I just want to prevent the heart failure, dementia, kidney failure, stroke and erectile dysfunction that result from the high blood pressure. If you give me a pill that magically improves the blood pressure but doesn't avoid those end-points I'm not interested.

But as the number game has become a larger part of medicine we are getting medications that are pursued and approved only for their ability to fix the numbers. Some have been super successful, statins have repeatedly and reliably shown their ability to reduce events in lockstep with reducing the cholesterol. Lately however, it is feeling like success of the statins to reduce LDL and also reduce cardiovascular events maybe more the exception than the rule.

The recent experience with ESAs and hemoglobin have been beat to death in the nephrology community. See this post for a deep dive. The core issue, is that low hemoglobins are bad for patients, but using ESAs to improve the hemoglobin does not mitigate the risk. And not only does it not mitigate the risk, it appears that the current agents bring with them novel arterial and venous thrombotic risks.

The experience with A1c seems to be playing out using a similar script. Glitazones were approved based on their ability to reduce blood sugars. They effectively lower blood sugar but Rosiglitazone increased the risk of cardiovascular death by 64% and was associated with increased composite outcome of stroke, heart failure and total mortality compared to pioglitazone.

And June 9th pioglitazone was pulled from the shelves in France for increased risk of bladder cancer. A position validated by the FDA on June 15th.

This comes on the heals of three studies in 2008 and 2009 that question the notion of very tight (less than 7%) hemoglobin a1c targets to improve patient outcomes.

In cardiology, following the stunning success of statins and LDL we have a string of failures, Ezetimibe (Zetia/Vytorin) for LDL and niacin/torcetripib for HDL

I often feel the only reason we still treat PTH is that no one has done the study to show that it helps and when we get around to that trial, I'm looking at you Abbott, we will find that it too, has been a waste of money and attention.

Great presentation on using diagrams in presentations

2011-07-18T22:50:00.000-04:00

Good advice on making tidy diagrams for your killer presentation.

How to make Awesome Diagrams for your slides

View more presentations from otikik

Hyaline casts

2011-07-08T11:32:00.002-04:00

We just got our microscope serviced. It works great.

- Posted using BlogPress from my iPhone

Must read article on funding for antibiotic resistance

2011-07-07T12:08:00.000-04:00

Maryn McKenna writes about NIH funding for highly resistant bacterial infections. The data comes from a poster by Eli Perecevich (Blog) and ML Scweizer.

The investigators looked at funding into Enterobacter species, MRSA and other resistant staph, C. difficile, Acinetobacter baumanii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterococcus faecium as the definition of resistant organism research. In 2009, the NIH spent $398 million. For comparison, in 2007 the NIH spent $1.24 billion dollars on HIV research.

Perecevich and Scweizer then compared the mortality from the different diseases and the relative amount of money spent on them (see graph at right).

Though 95% confidence intervals or P values were not provided, the difference appears significant.

The easy explanation is to blame the politics of AIDS. HIV infection, like breast cancer, is a disease with a well organized and loud constituency and they have labored hard to get funding. Unfortunately that funding comes at the expense of other diseases that may be less visible despite having equivalent impact.

The other cynical answer is to blame capitalism. The fact that HIV treatment is lifelong makes it very profitable for drug companies to focus their research on anti-viral treatment, especially compared to acute bacterial infections that may require only 10 days of treatment. I have secondhand knowledge that in the world venture financed early drug research this is very important, however, these are NIH dollars, which should not be influenced by potential profit.

I think the answer is that the market for drug resistant infection is driven by the availability of good grant requests and interested researchers. For 30 years the best and brightest ID researchers have been going into HIV research, it will take a while to turn that battleship to other areas of interest. Supporting this theory is the fact that research on resistant organisms increased from $180 million to $398 million from 2007 to 2009. So interest and money are being directed to this field but it will take time.

Stupid iPhone tricks: auto-dialing into a phone maze

2011-07-07T08:00:00.000-04:00

The phone system in my office allows patients, hospitals and practitioners to leave messages and then calls to alert us about new message. Retrieving the message is a multistep process:

call the main office number
dial a prefix plus my extension
dial my password
enter the code to play back my messages

You can program an iPhone to playback a telephone script to do this. This is a huge aggravation saver.

Create a new contact with an appropriate name

Enter the voicemail number and then tap the bottom left button

This brings up an alternate keypad with 5 buttons

The wait button inserts a semi-colon and the pause botton inserts a comma.

A "wait" will delay sending the next numbers until you tap a button, a pause will delay the next numbers by a second or two. This is what a semicolon looks like when dialing a number:

I use a pause until the phone picks up and then insert a pause after each step so the phone number looks like this:

(313) 886-8787 ; extension , passcode , play-back code

This trick works great.

I love the smell of July 1st in the morning

2011-07-06T11:55:00.001-04:00

As has been the tradition since 2008, I had the honor of giving the morning report on July 1st for the St John Hospital and Medical Center Internal Medicine Residency Program. July one, openning day of the academic year. The conference room was crackling with the energy of fresh interns and the equally excited second years ready to run their own teams.

Giving the lecture was a lot of fun. There were a lot of insightful questions, some because the questioner is terrified and others to show how smart she is. Nobody looked sleep deprived, so the ratio of deer-in-the-headlights to asleep-at-their-desk was unnaturally high.

The lecture covered three topics:

total body water and how to choose an IV fluid
diuretics
dysnatremia

There is no way I could get through the deck in the 50 minutes of time we had. It probably would take 90 minutes to cover it all. In delivering the talk I focused on the mood of starting this great adventure.

Here are some tips to using this presentation:

The first slide has Munch's Skrik, which I explain translates as July 1st

Slide 4 has my favorite quote about kidney function. Homer Smith essentially uses 150 words to explain the point that the job of the kidneys is not to make urine anymore than the job of a factory is to make smoke.

The lungs serve to maintain the composition of the extra-cellular fluid with respect to oxygen and carbon dioxide, and with this their duty ends. The responsibility for maintaining the composition of this fluid in respect to other constituents devolves on the kidneys. It is no exaggeration to say that the composition of the body fluids is determined not by what the mouth takes in but what the kidneys keep: they are the master chemists of our internal environment. Which, so to speak, they manufacture in reverse by working it over some fifteen times a day. When among other duties, they excrete the ashes of our body fires, or remove from the blood the infinite variety of foreign substances that are constantly being absorbed from our indiscriminate gastrointestinal tracts, these excretory operations are incidental to the major task of keeping our internal environments in the ideal, balanced state.

Homer W. Smith from From Fish to Philosopher

Slides 5-9 emphasize that this topic is not a niche topic, the issues of fluids and electrolytes comes up everyday, on every patient.

Slide 11, warn everyone that the unfortunate person who gains 30 kg in this slide is a medicine resident gorging on donuts at morning report.

Slide 18, remind everyone that LR is for surgeons. Deny any knowledge of the reason for this peculiarity. Explain that this is further evidence that they are an alien species unrelated to hard working, honest IM docs.

Slide 27 Explain that the question, "Would you give a drowning man a glass of water?" was taught to me by one of the most foul-mouthed senior residents when I was an intern. I want to show that the lessons learned this year will be the stories you tell interns decades later. Interns will learn more this year than any other year of their life, except their first year of life.

Slide 29 recommend everyone read House of God.

Here is the lecture in PDF and Powerpoint

Muddy brown cast via iPhone 4

2011-07-06T08:07:00.001-04:00

Using the instructions from the NEJM I captured this muddy brown cast in a patient with acute on chronic acute kidney injury. I love this new tool.

The new definition of a rock and a hard place--Updated

2011-07-05T10:38:00.001-04:00

The rock would be Amgen with their newest prescribing information for Epogen and Aranesp. The recommendations for dialysis patients can be summarized as:

Specifically, for patients on dialysis, the label advises physicians to initiate ESA therapy when the hemoglobin level is less than 10 g/dL and guides physicians to reduce or interrupt the dose when the hemoglobin approaches or exceeds 11 g/dL. So target a hemoglobin higher than needed to prevent transfusions and no higher than 11 g/dL.

The hard place would be the federal government whose Quality Improvement Plan (QIP) for dialysis units states:

The intent is to control anemia and maintain optimum hemoglobin levels within the range of 10-12 g/dL (grams per deciliter). Anemia management will be assessed by two separate measures:
CMS will assess the percentage of patients whose hemoglobin levels dipped under 10 g/dL. The program assigns this measure the greatest weight in facility performance calculation, because numbers under 10 g/dL are highly undesirable. (Weight = 50%)
CMS will assess the percentage of patients whose hemoglobin levels exceeded 12 g/dL. Numbers greater than 12 g/dL could suggest unnecessary or excessive administration of certain drugs. (Weight = 25%)

There is little air to breathe between 10 and 11 g/dL. Something has got to change and my guess is by the end of the year QIP will be suggesting hemoglobins between 9 and 10.

UPDATE: CMS has proposed new rules that remove the lower limit for hemoglobin as a quality measure. Here is some news coverage and here is the PDF.

I think its crazy to remove the lower hemoglobin limit. When CMS introduced the bundled payment system they turned anemia management from a profit center to a cost center for dialysis units. The Quality Incentive Plan was designed to prevent dialysis units from minimizing costs by denying patients adequate treatment. It seems that with the 2013 proposal, a Machiavellian dialysis unit could eliminate anemia management completely and reap financial rewards without penalty.

This can't be right, at the least CMS should add minimizing transfusions as a quality measure, that would reconcile the prescribing information and the quality goals.

Hat tip to the anonymous first poster.

Using an iPhone for capturing urine microscopy

2011-06-22T09:03:00.000-04:00

From the NEJM:

The authors describe their technique:

When microscopy revealed a field of interest, the camera was placed about 0.5 to 1.0 cm over one of the eyepieces, allowing optimization of the image and light intensity by means of the camera's digital display. The auto-focus and exposure features generally produced a circular image surrounded by a black rim...

Can't wait to try this.

Hat tip Pediatric Nephrology

Article on aging I want to spend some time looking at

2011-06-20T12:08:00.000-04:00

From the American Scientist: Aging: to Treat or Not to Treat?

Patient called me with a blood pressure of 170

2011-06-16T11:19:00.000-04:00

He has resistant hypertension that has been well controlled since we added spironolactone. He reported that his systolic blood pressures were between 170 and 205 over the last three hours. In the morning his blood pressure was 120 and for the last week he had been getting blood pressures of 115 to 135, trending toward the lower end of that range.

I told him that I wasn't worried about the isolated spike in blood pressure. The goal of therapy is to get the average blood pressure down and that chasing individual isolated episodes of hypertension becomes a hopeless game of whack-a-mole.

The treatment of hypertension is like trying to change the climate, not control the weather.

What do you do when they get this phone call? Do you chase after elevated blood pressures with prn clonidine? Is there an evidence based approach to this?

How many cancers have you caused from ordering CT scans

2011-06-14T16:42:00.000-04:00

It feels like if a patient coughs they get a CT angiogram to rule-out pulmonary embolism. How many patients would defere that test if they had to sign off on the following chart:

Makes you think twice regarding the CT for stone-profile that some patients get yearly "just to make sure the Urocit-K is working."

Hat tip to Academic Life in Emergency Medicine blog.

If you are giving a commencement speech be original, don't steal

2011-06-13T16:17:00.000-04:00

Arrogant? Stupid? Both?

Incredible story today comes from the University of Alberta Medical School where the dean, Phil Baker, plagiarized Atul Gawande's Stanford commencement address from 2010 during U of A's own graduation ceremony. My favorite part is the students using iPhones to discover the intellectual property theft during the speech:

"A couple of the students recognized the term 'velluvial matrix,' which is in Mr. Gawande's speech," said class president Brittany Barber. "They Googled it on their phones.

For anyone to think they could rip-off a high profile author in this day and age is the height of arrogance and or stupidity.

Epo, anemia and the lack of placebo controlled trials

2011-06-10T11:44:00.002-04:00

By a mistake of communication I was scheduled to give the anemia talk at a recent chronic kidney disease symposium. I would have never selected this topic on my own. I work with Robert Provenzano, one of the Gods of Anemia. Fortunately, this was a happy accident. I loved researching and writing this presentation. The whole experience was an important lesson on the value of working out of your comfort areas.

The anemia saga is well known to all nephrologists and is covered in depth in my presentation but let me recap my version of the story.

Life before Epo was pretty bad. the average dialysis patient received a transfusion more years than not. On the Eve of Epo the transfusion was rate was 16% per quarter!

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter is a 98% reduction in transfusions. Revolutionary. And this doesn't even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

I was in college when this happened and it's a little hard to imagine how exciting that must have been. The introduction of Epo launched a million observational trials that all pointed in the same direction:

Where you found higher hemoglobins you found better patient outcomes.

It almost didn't matter what outcome you were interested in: hospitalizations, mortality, regression of left ventricular hypertrophy, quality of life, fatigue score. It didn't matter, everything was better with higher hemoglobins. I suspect the community was seduced by the observational results but for what ever reason the amount of randomized controlled trial data that emerged was laughably small. By 2007, Epo was eating up 1.8 billion Medicare dollars. It should have been the best studied drug and instead it was among the least studied.

I tried to find Henry Paulson's signature but had to settle for George Bush's.

Here is the table from K/DOQI anemia recommendations where they summarized all of the RCT data from the birth of Epo through May 2006 (apparently it omits a single 2005 study).

8 Epo vs Epo studies and 3 placebo controlled trials, 1 placebo controlled trials in pediatrics

The paucity of placebo controlled trials is shocking. No one demonstrated that higher hemoglobin targets had a mortality benefit or regressed LVH compared to placebo. This would not be so problematic if the Epo vs Epo studies had been positive, but those too were negative trials. So we are in the awkward position, a quarter century after the introduction of EPO we cannot conclusively state that the drug does any more than reduce transfusions and improve quality of life. All the mortality reductions, cardiovascular disease protection amount to observational-backed hype (one small rct (N=38) study did show a reduction in LVH).

Favorite slide from the deck

Part of me is outraged but another part understands how difficult it would be randomize dialysis patients to placebo. I couldn't, in good faith, expose trial subjects to the transfusions, fatigue and weakness that being randomized to the placebo-arm would entail. It fails my personal "Grandma test" (i.e. Would you feel comfortable enrolling your grandma in a placebo controlled trial of Epo? No). I understand that and forgive the dialysis researchers; however I am a little disturbed to witness how in the pre-dialysis CKD population the same pattern of relying on observational data. In CKD these is no transfusion epidemic that needed to be derailed, there is no profound fatigue turning patients to zombies. We had an opportunity to do the right studies to figure out if this expensive Nectar of Thousand Oaks really helped. The paucity of placebo controlled and randomized controlled trials in pre-dialysis patients is embarrassing.

Reading this editorial by Marc Pfeffer crystalized this critical mistake. I spent a fair proportion of the presentation laying out how statins evolved from being used in only the sickest patients to larger and larger populations and how at each step placebo controlled trials were used to prove efficacy. Not every step was a win, statins for heart failure failed, but the key is that cardiologists know that statins don't improve heart failure because they tested it with two (1, 2) placebo-controlled trials.

Why is nephrology lacking the randomized controlled trials that have defined the huge advancement in cardiovascular disease over the last 25 years?

It isn't due to the severity of illness, the first placebo controlled trial of ACEi in heart failure used a cohort with 40% mortality at 6 months.
It isn't timing, ACEi for heart failure was developed and proven at the same time as the introduction of Epo.

I don't know the why but I have a couple of theories. One is the richness of the retrospective data in nephrology, brought to us by the USRDS, blinds us to the importance of prospective data. This could explain why are repeatedly burned by observational studies, see: kT/V, vitamin D, and binders.

The other theory is that, unlike statins and ACEi where there are many vendors producing drugs in the class of interest, there is a total monopoly in the field of ESA. You want to increase the hemoglobin you need to buy Epogen. No generic, no competing ESA. In the ACEi market, having enalepril as the drug studied in the CONSENSUS and SOLVD trials paid huge dividends to Merck. Having in-class competition lead to commercial support of critical research. Amgen had no need for this because the US Patent Office gave them a monopoly. A monopoly that seems to last forever. Why is it that every other drug from the late 80's is generic: omeprazole, captopril, enalepril, benazepril, metformin, simvastatin, etc. Even drugs from the 90's are now generic: losartan, lansoprazole.

Epogen stands alone without generic competition. And unfortunately, largely without placebo controlled trials to back-up mountains of hype.

The deck can be found here: Keynote | PDF

The most difficult decision: Palliative care

2011-06-09T11:35:00.000-04:00

I was peripherally involved in a patient with end-stage heart failure. We were consulted for hyponatremia. The patient had a sodium on 120 which we helped increase to 130. During our involvement, the family was wrestling with choosing palliative care. The patient was frail with advanced dementia.

The patient ultimately died in the hospital before being made comfort care. The family was relieved that he passed. I was struck by the question, that if the family was so relieved that he passed why was it so difficult to decide on palliative care.

In all the intensity of care conversations I have been involved in, I can't remember the principal asking the family to imagine how they would feel if that got a call from the hospital that their loved one had passed. And then add, that if the feeling is one of relief, that hospice, or DNR, or palliative care, is probably the right decision.

I need to get this font

2011-06-07T08:31:00.001-04:00

Inspired by the title credits from Dr. Strangelove: Strangelove typeface

Here are screen captures of the title credit sequence:

Not "Death by PowerPoint" but "Death Star by PowerPoint"

2011-06-06T11:26:00.000-04:00

I love this scene in Star Wars because it is pretty rare in movies to see a formal lecture. The presenter, General Dodonna, knocks it out of the park.

What if the Dodonna used Powerpoint?

Garr Reynolds from Presentation Zen deconstructs Dodonna's presentation style and compares it with contemporary powerpoint presentations. FYI, anyone who wants to do a better job creating and delivering presentations should be reading Presentation Zen.

Here is a movie with the same idea from YTMND:

Mixed acid-base disorder and altered mental status

2011-06-04T08:16:00.000-04:00

An 80 year old woman was readmitted to the hospital with mental status changes. She was recently discharged following successful treatment for heart failure and associated fluid overload. Her discharge medications were as follows: (You know the joke: senior asks the intern, "What medications is she on?" And the Intern looks up and says, "uhm, all of them.")

She was brought to the ED with a week history of increasing confusion and weakness. The patient had some shortness of breath but this was typical for her baseline.

Initial labs:

The ABG showed:

pH: 7.47
pCO2: 71
paO2: 74
HCO3: 51

First look at the pH

It's elevated so this is a alkalosis

Look at the bicarbonate and the pH

If they both are moving in the same direction it is metabolic
If they are moving in opposite directions it is resiratory
Here the pH and bicarb are up, so it is metabolic

Put the two together and identify the primary disorder:

Metabolic Alkalosis

Calculate the predicted pCO2 from the bicarbonate

Calculate how far the bicarbonate has increased, this is the delta bicarbonate
Take two-thirds of the delta and add it to 40, the normal pCO2
In our patient the bicarb has risen from 24 to 51, a delta of 27, two-thirds of that is 18, so the pCO2 should be 58 +/-2

Is there a second primary disorder affecting the pCO2?

Compare the predicted pCO2 to the actual pCO2
If the actual pCO2 is lower than predicted, the patient has an additional respiratory alkalosis
If the actual pCO2 is higher than predicted, the patient has an additional respiratory acidosis
Our patient's actual pCO2 of 71, is way higher than the predicted 58+/-2.

The complete interpretation of the ABG is: a primary metabolic alkalosis with an additional primary respiratory acidosis

The ED diagnosed her with acute hypercarbic respiratory failure, and blamed the mental status changes on CO2 retention. She was started on bipap and admitted. The following day her pCO2 improved to 50 but she had persistant confusion. At that point we were consulted for acute renal failure, and noted that she had severe hypercalcemia, calcium of 14.7 mg/dl.

Her phosphate was 1.9 and subsequent work-up showed a PTH of 20., with normal 25 OH and 1,25 OH vitamin D.

On the basis of a combined metabolic alkalosis, acute renal failure, normal PTH and elevated calcium we diagnosed her with Milk-Alkali Syndrome, and started her on IV normal saline and SQ calcitonin. We did not give steroids or bisphosphonates. Over the ensuing four days her calcium drifted down to 10.1. On the third day her sensorium cleared.

Our patient seems to perfectly match the modern form of Milk-Alkali Syndrome or Calcium-Alkali Syndrome using Patel and Goldfarb's suggested nomenclature. The calcium and alkali were both supplied by calcium carbonate. Additionally she was on a thiazide-type diuretic which decreases calcium excretion. The classic 1930's form of Milk-Alkali Syndrome was associated with high phosphorous levels while the contemporary form has hypophosphatemia. The principle difference comes from the source of calcium:

In classic milk-alkali syndrome the patient is calcium loaded from milk, which is very high in phosphorous (370-450 mg per 8 oz)
In contemporary milk-alkali syndrome the calcium carbonate provides the calcium and also acts as a phosphorous binder to prevent dietary phosphorous absorption.

According to Patel and Goldfarb, the hypophosphatemia is more than just a spectator, it's integral to the modern disease. The low phosphorous stimulates conversion of the storage form of vitamin D (25 OH D) to the active form, (1,25 OH D) which further enhances GI calcium absorption:

Low phosphate levels stimulate the renal metabolism of calcitriol and, consequently, absorption of calcium by the gut. Levels of 1,25-hydroxyvitamin D in patients with the calcium-alkali syndrome, of course, are generally low in the setting of hypercalcemia, although some are in the low- normal range and perhaps inappropriately high. These latter levels may depend on previous exposure to vitamin D supplementation, because vitamin D is often added to some over-the-counter calcium preparations, but more epidemiology is needed to clarify this exposure.

Editor snark, I love the sentence: "Levels of 1,25-hydroxyvitamin D in patients with the calcium-alkali syndrome, of course, are generally low in the setting of hypercalcemia, although some are in the low- normal range and perhaps inappropriately high." So the levels arer either low, normal or high. Thanks for clearing things up.

The contemporary modern patient is typically female, and post menopausal. Other susceptible populations include cardiac transplant patients, pregnant patients, and those with calcium-rich food-fetishes (reported in anorexic nervosa patients).

Though the alkali and calcium are typically exogenous, diuretic-induced alkalosis can contribute to the condition, and doubly so, if the diuretic is a thiazide which decreases renal calcium losses. NSAIDs contribute by lowering GFR.

The Ca sensing receptor (CaSR) in the thick ascending limb of the loop of Henle binds calcium and binds it more avidly with alkalemia. Binding of the calcium sensing receptor shuts down the ROMK channel which decreases sodium reabsorption and increases urinary loss of calcium. Hypercalcemia, by activating the CaSR, acts like Lasix.

The loop-diuretic effect furthers volume deficiency, which, along with direct calcium-induced vasoconstriction, worsens the renal failure. Volume deficiency also stimulate calcium reabsorption in the proximal tubule.

Increased tubular calcium stimulates TRPV5, the principle calcium transporters in the distal nephron, decreasing renal calcium losses and furthering the hypercalcemia. The TRPV5 is also enhanced by the alkalosis.

Volume expansion with sodium chloride is the bedrock of therapy.

Do not miss the excellent and short review in JASN.

PBFluids is three

2011-06-02T17:29:00.001-04:00

I'm such a bad parent. I forgot PBFluids birthday. The first blog post was May 30th 2008. 1,098 days ago. This is post number 390. The volume has tappered off recently but i still have the blogging fire in my belly I just have been working on some other projects: meaningful use, grand rounds, fellow teaching, and an upcoming primary care symposium.

It's been a fun trip. Here's to three more years of blogging!

Fructose, hypertension and CKD: an update

2011-06-01T22:06:00.000-04:00

Today, I gave grand-rounds at William Beaumont Hospital Royal Oak. I gave the fructose-uric acid lecture I gave in January of 2010.

Over the last 16 months, the science has continued to move forward without any hiccups. Additionally, data supporting direct renal toxicity of fructose and uric acid has matured. This latest version of the lecture adds a section on CKD including a summary of both randomized-controlled-trials examining allopurinol to reduce the progression of chronic kidney disease.

The lecture is available in the under the lecture tab.

Corticotropin for acute gout

2011-05-31T11:51:00.000-04:00

I had never heard of this:

Corticotropin shares the same profile of indica- tions as systemic glucocorticoids: polyarticular flares in which NSAIDs are not effective or contraindicated. However, corticotropin is more costly compared with generic glucocorticoids and not as widely available. Its mechanism of action seems to be through stimulation of endog- enous adrenal hormones (63, PDF); however, direct anti- inflammatory effects at the affected site also have been postulated (64). Corticotropin is available for subcutaneous or intramuscular adminis- tration, and a single dose of 40 IU is rapid, efficient, and well tolerated, even in patients using moderate doses of oral glucocorticoids (65, 66, 67) Adverse effects include mild hypokalemia, fluid retention, hyperglycemia, and the development of rebound arthritis; the latter is controlled by administration of prophylactic low-dose colchicine (if possible).

Source: Gaffo and Saag. Management of hyperuricemia and gout in CKD. Am J Kidney Dis (2008) vol. 52 (5) pp. 994-1009

Anybody doing this?

Highest TTKG with hypokalemia

2011-05-28T09:00:00.000-04:00

Patient with a lifelong history of hypokalemia. He came to me for a second opinion, his previous nephrologist had been nudging up his potassium dose on every visit and the patient was now on 70 mEq of KCl daily and was getting uncomfortable with endlessly increasing doses of potassium.

At the time I saw him these were his labs (he had decreased his potassium supplementation to 20 mEq/day):

Blood

sodium: 128
glucose: 90
potassium: 2.8
Creatinine: 0.9
BUN: 11
Magnesium: 1.8
Calculated osmolality: 265

Urine

sodium: 135
potassium: >100
Osmolality: 637

Trans-tubular potassium gradient: 14.9. That's crazy high for a patient with hypokalemia, one should expect it to be less than 2 for hypokalemia of extra-renal origin, and only 7 or 8 for hypokalemia from hyperaldosteronism. Halperin et al. were not able to get the TTKG that high even when they took normokalemic patients and doped them with fludrocortisone and 50 mEq of oral potassium.

And that 14.9 is assuming the urine potassium is 100, our lab doesn't do serial dilutions so who knows what the actual potassium is? 120? 140?

I'm still waiting for the renin and aldo but I smell some Bartter's

Fellow-Level Lecture on Hyponatremia

2011-05-26T21:43:00.000-04:00

Today I did a noon conference on sodium for the neph fellows. Instead of a comprehensive sodium lecture I focused on a number of different elements and interesting aspects of hyponatremia. Mostly a deeper dive into aspects that you don't have time to cover in standard sodium lecture.

I opened with 17 quick slides on free water clearance. These slides are old and I think I could do better. Definitely due for an update.

Download the slides here.

Then I used a slide deck which covers:

mannitol as a cause of an osmolar gap and pseudohyponatremia
glycine induced pseudohyponatremia
a bit of data on rapid correction of sodium by hemodialysis
exercise induced hyponatremia
use of FeNa and FeUrea and FeUric acid to distinguish between salt depletion and SIADH

download the slides here

It was a fun lecture and everyone participated in a casual and interactive freewheeling learning session. Great stuff.