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Reata, a no show at ASN Kidney Week

What do you do when your tentpole molecule fails it’s phase three clinical trial? I guess you don’t even build your booth at Renal Week.

At Kidney Week 2010 in Denver, Reata presented the results of BEAM, the phase II trial of bardoxolone as part of the late breaking clinical trial data. They shocked the world by showing increased GFR in diabetic nephropathy. The data was published in the NEJM in July 2011. But even before publishing they began work on the phase III trial, BEACON.

I can attest to the excitement that BEACON generated. I was not an investigator but I did enroll one patient in the trial and even had friends calling me trying to get loved ones in the trial. I outlined my experience with bardoxolone in the diabetic nephropathy talk that I gave to the Michigan State Medical Society (Keynote | PDF). On October 18th, Reata terminated BEACON due to “excess serious adverse events and mortality.”

Unfortunately, October 18th was only 2 weeks before the Start of KidneyWeek 2012, the premier nephrology conference in the U.S. Reata had already signed on with the American Society of Nephrology to be a Diamond Level Sponsor:

Not only were they a Diamond Sponsor, but they had bought top billing on the Abstract Book with a full page ad on the back cover:

The ad implores you join them at booth 1529. I went by there just to see how the company would try to spin this disaster. But there was no booth 1529. The map shows it between Amgen and Otsuka, but there is just a pharmacy and an EMR company in its place. It’s like the opposite of when Obi-Wan goes to Yoda trying to find the Planet Kamino.


Lost a Planet Master Obi-Wan Has

Poor Reata. Evidence-based medicine can be such a bitch.

I’d show pictures, but taking pictures of the booths is forbidden by ASN policy. Whisky Tango Foxtrot

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Saline versus Ringer’s Solution. Fight!

Internists use normal saline.
Surgeons use lactated ringers.

Its a cultural difference, perpetuated by dogma.

Here’s how Burton Rose characterized Ringer’s solution in his classic Clinical Physiology of Acid-Base and Electrolyte disorders:

This what I was taught. That is what I teach and this is what I believed, but I’m turning.
METHODS
The Study was a bundle-of-care study, in which a number of practices were changed all at once. The study was conducted in a single ICU at the University of Melbourne. For six months outcomes were tracked with usual care to act as the control group, then the bundle was phased-in and after 6 months, they tracked a second 6 month block to represent the experimental group. By spacing the control experimental groups as they did, they eliminated seasonal variation in illnesses. 

During the control phase, physicians were able to prescribe IV fluids per personal preference. During the experimental period, chloride rich solutions were restricted to specific clinical conditions: hyponatremia, traumatic brain injury and cerebral edema. Otherwise patients were given low chloride solutions: Hartman’s solution, plasma-Lye 148 and 4% albumin.

The primary outcome was the change in creatinine and incidence of AKI, using RIFLE criteria. Secondary outcomes included need for acute dialysis, length of of ICU and hospital stay and survival.

RESULTS

The study consisted of 1644 admissions to the ICU, 760 in the control period and 773 in the experimental period. The two cohorts were well matched with significant differences only with metabolic diagnosis being more common in the control period (7 vs 4.4%) and neurologic disorders being more common in the experimental period (6.2 vs 8.8%).

The difference in the fluids being used was dramatic and this resulted in significant differences in electrolyte exposure:

The authors demonstrated a statistically significant difference in the change in serum creatinine,(increase of 0.25 in the control group vs 0.16 experimental group) which is of questionable clinical significance. More impressive was the decrease in AKI by RIFLE criteria.
With Cox proportional hazards model adjustment they found a hazard ratio of 0.52 (P=0.01) for AKI.
The authors actually use a modified RIFLE criteria as they only used changes in serum creatinine and ignore changes in urine output. This is convenient as most of the studies that have validated the RIFLE criteria have likewise used creatinine limited criteria. As a refresher for those of you sleeping in AKI class here is how the RIFLE criteria grades AKI: 
The most important finding was a decreased need for acute dialysis: 78 patients during control versus 49 with the low chloride bundle (P=0.005).
There was no difference in length of ICU or hospital stay, and no change in survival.
In the discussion the authors acknowledge that their study design precludes a deep analysis of what was responsible for the reduction in AKI. By changing nearly all of the fluids at the same time it is difficult to assign blame to any one change. Was it the decrease in chloride? Or the increase in alkali? Increased potassium? Despite this limitation the authors provide the rational for blaming chloride for AKI.
They point out that chloride in normal saline is no where near physiologic at 154 mEq/L. They point to observational study data showing decreased dialysis with Plasmalyte compared to saline.  Animal studies showing better cortical perfusion with decreased chloride exposure. They suggest that Tubulo-glomerular feedback maybe responsible for this. 
Tubulo-glomerular Feedback is the driving principle behind the theory of Acute Renal Success. Acute renal success is a theory which attempts to explain the conundrum of oliguria in ATN. Patients with ATN have intact glomeruli, yet in some cases they have a GFR of zero. Why do normal appearing glomeruli cease to filter? They cease to filter because if the they did, the damaged tubules would not be able to reabsorb the filtrate and the kidney would excrete all of the body’s plasma in about half an hour.
The glomeruli can only safely filter 100 ml per minutes if the tubules reabsorb 99+% of that fluid. In ATN that reassurance is lost and the intact glomeruli need a way to detect the failure of reabsorption. Chloride sensors in the thick ascending loop of Henle signal the glomeruli to decrease filtration when activated. So in cases of ATN, the glomeruli initially filter normally but when the proximal tubule and Loop of Henle fail to reabsorb the chloride, chloride floods these receptors triggering a feedback mechanism to shutdown the glomeruli associated with that tubule.
In this article the authors suggest the non-physiologic, high chloride solutions we use in patients may result in excess chloride delivery to the thick ascending limb of the loop of Henle triggering tubulo-glomerular feedback decreasing GFR. 
This is an intriguing paper and I look forward to more data, even if it means the surgeons were right.
Update: Jim Smith and I had a great back-and-forth on this. Open this link to follow all of the fireworks.

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Thoughts on QR codes at Medical Conferences

I am just back from Med 2.0. It was a great conference that did so many things right. One of the things that was right, was that every talk, every poster, every rapid fire session has its own web page. Here is what the top of those pages look like:

The square in the upper right, if you’r are not familiar, is a QR-code. All posters are supposed to use this label and all presentations are supposed to display this graphic on the title slide. When you scan the code with a smart phone (you can find an excellent free, QR-scanner for the iPhone here, life hacker endorsement of said scanner here), the smart phone will open up the web page for the talk or poster. Cool idea. Unfortunately, it was poorly executed by most presenters. Here is a typical title slide:

Using my iPhone from my seat in the middle of the auditorium, I had no chance of getting an accurate scan. Since I am one of those annoying conference participants who photographs every slide, I have found myself scanning my MacBook screen to get the links. Absurd, and really no easier than using the conference website to search for the presentation page. The right way to do it is the way John Ainsworth did it in his presentation on using Drupal to create a low tech, no software, SMS-notification system across 11 countries, 6 languages and 3 time zones:

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Medicine 2.0: Conversations from the hallway

This week-end I am in Boston at the Medicine 2.0 Conference. It has been awesome. I am tweeting and bloggin about it at eAJKD (blog | Twitter)

At one of the sessions on medical education, I made a comment on Beaumont’s mandatory medical student attendance. Afterwards, Brian Alper, the founder of DynaMed came up to me to talk. He started to tell me about Dynamed, I told him I was familiar. When I was working with the students on the Team Based Learning, a number of them told me how much they loved the product. They even told me that it was better than UpToDate, a statement that gave me chest pain.

I had to tell him about my terrible experience looking up Goodpasture’s in Dynamed. He looked at me and said, “So, you’re the one.”

He was totally professional and pulled up the current version of the topic on his iPad. Wow! What a change. The topic looks completely rewritten and in a comprehensive style. It now has an author, a wide variety of treatment options including plasmapheresis and immunosuppressants. He told me that he would email me the topic. I plan on revising my review of DynaMed, but for now all I can say is that it looks a lot better.

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Chicken Noodle Soup versus Normal Saline. Fight!

More than a few times this week, I have found myself prescribing Jewish Penicillin, chicken noodle soup. CNS is rich in sodium so it is just about the best way to prescribe volume repletion in the out-patent arena. So i was delighted to see one of the dietician students projects on display in the hospital:

1720 mg of sodium per can of Swanson 100% Natural Chicken Broth (two 240 mL servings per can). So how does that stack up against old faithful, normal saline?

Normal saline has 154 mmol of sodium per liter or 3,542 mg of sodium per liter (154 mEq x 23 mg per mmol, the molecular weight of sodium), so a can of chicken soup is equivalent to about half a bag of normal saline.

Update: I don’t get many good comments on Blogger but I got this pitch perfect comment on Twitter:

@kidney_boy Nice. Didn’t fully appreciate that a bag of saline was 3.5gm Na! Makes me laugh thinking of the 2gm Na diet pts getting IVF!
— Aaron Logan (@pyknosis) September 15, 2012

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Team based learning, reason for optimism about medical education

In general, as I have progressed through my education, I have felt that the quality of education has been on a downward vector.

  • I believe that duty hour work restrictions have diminished continuity of care and reduced the drive for residents to read and learn about their patients, because the patients feel less like “their patients.”
  • I think the emphasis on fraud prevention that has meant that attendings need to see and be present for all of the meaningful aspects of patient encounters has diminished fellow autonomy and delayed the maturation process that senior residents and fellows undergo.
  • I think the addition of alternative medicine curriculum to medical schools is an inexcusable retreat from the goal of medical scientists.

But I have recently experienced a vision for the future of medical education at Oakland University William Beaumont Medical school and I am blown away. Don’t worry future doctors are going to be just fine.

OUWB is one of the newest medical schools in the country and has it’s first two classes of medical students enrolled, classes of 2015 and 2016. The second years are finishing up the renal section. It is an integrated unit including histology, pathology, physiology and pathophysiology. I was privileged to have an integral role in developing the curriculum. One of the parts that I spent hours on was developing Team Based Learning modules (TBL).

Typical MD Lab from Scott Hall
(http://conjoint.med.wayne.edu/mdlabs.php)

Team based learning is OUWB’s version of the small group learning sessions that have always been a part of the first two years of medical school. During my years at Wayne State they were called MD Labs. The sessions were sprinkled through out the curricula. I went to a few and they were of widely variable quality. I didn’t go to many, because they didn’t count toward your grade. That told me that The Dean didn’t think they were important enough to count so I took the hint spent my limited hours cranking on stuff that counted.

The TBL is a reinterpretation of those small group sessions that I see as wildly successful. The success is not by accident and comes from the novel structure of the sessions. A TBL is made up of preparation and three segments:

Prep

The preparatory reading is a chapter, or article or handout that covers all of the main ideas of the session. For proteinuria and glomerular disease the students were assigned a chapter in Harrison’s. For CKD and AKI the students were given review articles in BMJ (Hilton R. 2006) and NEJM (Abboud, Henrich 2010). For Sodium and Water, I wrote a 41 page chapter on the subject. Be warned I have been told that it has a lot of typos.


    Individual Readiness Assessment Test (iRAT)

    As soon as the session starts the students have a multiple choice test of 10 questions. All of the answers should be found in the assigned reading. The test score is part of the students grade in the section. This means that all of the students need to do the prep work and all of the students need to show up for the session. Two huge improvements to the Wayne State MD labs.
    Gunning for grades on the iRAT

      Team Readiness Assessment Test (tRAT)

      After completing the fill-in-the-bubble iRAT, the students then work in 5 person teams on the exact same questions they just answered. The teams have scratch off pads that work like instant lottery tickets with the correct answers. When the team answers a question they get instant feedback if they were right or wrong. This is closed book but the students all work together. After the all of the teams complete their tRAT there is a brief discussion of any questions that were troubling. The proctors walk around the room during the exercise and listen to the team discussions to they get a sense of what questions are difficult/poorly written.
      If you scratch off three horse shoes you win $60.
        Look at her notes. Every tricky nephrology
        question starts with “let’s draw a nephron.”

        Application Exercise

        Application questions are complex questions that supposed to integrate physiology and clinical medicine in to a complex multiple choice question. The questions are all open book, and in this age of WiFi, laptops and the WWW, we should really rename open book as open Google. The teams get 15-20 minutes per question and then simultaneously display their answer. Then the proctors lead a discussion on the reasoning behind the answers and different strategies the teams used to get to the answer.

        The things I love about the TBL

        • It is part of the grade. Curriculum directors need to understand that the medical school curriculum has more information than is possible to learn and students are rational actors. They will sacrifice important but uncounted learning opportunities in order to prepare for counted exams. There is no way to make something meaningful without making it part of the grade.
        • The iRAT happens right when the students walk in to the room. I love how this makes it clear that the students are being graded on preparation. The important thing is getting the students to learn the material before the session starts. This paragraph from Regis School of pharmacy states it perfectly:

        “To promote active and collaborative learning, students are sometimes asked to work in groups in class or on projects outside of class. While group work does benefit student learning, unfortunately it is often plagued by “social loafers”, or students who do not pull their weight in terms of helping the group. As a result, many students learn to dislike group work and may seek to avoid it. TBL is different. TBL ensures that each member of the team is held accountable for their own learning outside of class. Students who do not prepare adequately before class will perform poorly on the iRAT and will not be able to contribute in a meaningful manner to the tRAT and application exercises. As a result, most students who would normally remain “social loafers” in a group learning project are instead quickly motivated to do the assigned work out of class in order to perform well on the iRAT. In addition, as teams work together and compete with other teams in the class, loyalty to the team develops among each member. This further motivates the “social loafers” to prepare outside of class so that they can contribute and help the team succeed.“

        In the cut throat world of medical school any system that allowed a “social loafer” to benefit from the group while contributing nothing would be a recipe for a short lived project. The iRAT gives a clear message: come to class prepared, or you will suffer.

        • The application exercises are open google. To me, this was the most interesting part of TBL. Clinical medicine is, of course, open book. Everyday I am consulting Dr. Google, Epocrates and UpToDate. My information gathering strategies were developed on the fly in my clinical practice. No one taught me these types of skills and no where in medical school were there any opportunities to practice hone them. The students of OUWB are working together, comparing notes, seeing which resources work best. I heard students explain the virtues of DynaMed (a POS in my opinion). I spoke with students who distanced themselves from Wikipedia until I told them I was a fan and had no reservations about using the crowd sourced encyclopedia. After hearing me extol its virtues they quickly changed their tune and agreed that it was easy to filter good from bad wiki pages (referenced, with mainstream journals, avoid political topics) and that the good ones never steered them wrong.

        People used, Google, Wikipedia, UpToDate and a strange
        resource called a “book” 

        Summary

        The portable computer revolution of iPads and smart phones allows us to bring the library to the bedside, it is time for medical schools to appreciate and embrace this pivot in the history if medicine. TBLs are the best example I have seen of of this.

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        Live Tweeting lectures

        Social media in health care is a fascinating and rapidly mutating field. One of things that makes it so interesting is that just as we start to master one set of tools, new ones arrive. Twitter is the latest tool to catch fire in the Healthcare Social Media arena. The real time nature of Twitter and the ability to have conversations with colleagues around the world is one of the most globe-shrinking experiences in which I have ever participated.

        Twitter is great for exchanging single ideas and single sentences, but as the thought becomes more complex, the elegance of Twitter breaks down. People are forced to send tweet after tweet to express an idea. As the tweet stream begins to lengthen, it should becomes obvious that Twitter is not the right tool for the job. We do not live in a world with only hammers.
        The quintessential example of this is the trend to “Live Tweet” meetings. Sometimes this is appropriate. For example when the meeting contains breaking news. This happens at the Late Breaking Clinical Trials session at Kidney Week. Here the presenters are providing the world with its first glimpse at new information. I remember live tweeting the Bardoxolone results 6 months before they were published in the NEJM. That however is not what we tend to see with people live tweeting a meeting. Usually it is a string of hopelessly unintelligible tweets trying to express the words, images, references and ideas of a presenter in 140 characters (actually it is never 140 characters because no live tweet is complete without the obligatory meeting hashtag, #KidneyWeek12)
        I have heard people defend live tweeting as a way of keeping notes for a meeting. It’s great that you are taking notes but if you think that twitter is as good way to archive information, you must be new here. Old tweets regularly disappear from the Twitter database or become functionally unobtainable within a few weeks. Writing your notes on the back of a business card that you stick to the coffee house bulletin board would be a more reliable way to archive your thoughts. Additionally, if you are taking notes, why go through the overhead of parsing them into 140 character thoughts and posting them?
        In the end, live-tweeting a meeting seems intellectually lazy. I think it is great for participants to take notes, think about the speakers and post their summaries or conclusions to the internet. I just feel that Twitter is a terrible way to do it. If you want to post longer thoughts, careful notes or thoughtful conclusion, it sounds like you might like blogging.

        On the other hand if you want to make snarky side comments about the use of Comic Sans in the presentation Twitter is the perfect tool.

        Pot meet Kettle. Kettle meet pot:
        I have agreed to live Tweet Med 2.0’12 in September for eAJKD. I am going to try and filter my tweets and use the tool rationally. I want to pair a modest bolus of tweets with short individual posts for each session in which I participate.

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        OUWB MS2 Renal Section Course Materials

        I am teaching at the Oakland University Beaumont Medical School in August. Here are the lecture materials I used.

        Sodium and Water PDF (for medical students, longer than the hand out of the same name I use for third years). This is the 40+ page handout for the TBL on sodium and water. Here is the file from pages in case you wanted to fix some of my typos: Pages

        Acid Base Long-ass lecture PowerPoint (3 hours of Acid-Base fun)

        Acid Base hand out for workshop pdf | pages

        NAGMA Cases this is the brief powerpoint of NAGMA cases as part of the Acid-Base workshop

        Excel table for doing Henderson-Hasselbalch, anion gap and adjusted sodium. Useful if you need to rite a lot of acid-base problems and you are stickler for ABGs that are, you know, possible.

        Fluids and Electrolyte Companion This is a 500 page opus I wrote a decade ago. Most of the pictures and concepts that I taught from come right from this book. The acid-base section holds up pretty well, as does the potassium section. The Sodium section is a bit more variable.

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        How well do you know the nephrology blogosphere?

        I was reading Andrew Sullivan’s The Daily Dish the other day and came across this blurb:

        The current Ryan budget will impact today’s seniors immediately, due to its cuts to Medicaid. I blog about dialysis; here’s how the Ryan budget plays out in the provision of dialysis:

        The blurb is from an e-mail and Sullivan does not name the author or give a link back. You should read the whole post. It is well written and very clear. The author opened my eyes about the importance of Medicaid to incenter dialysis.

        After I finished it, I wondered who the author was. After a minute I sent off an e-mail to my best guess and today I received an e-mail telling me I was right.

        Can you guess the author. Put your guess in the comments.