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Biochem 411 with Dr. Beyer

Just about anyone who was pre-med at the University of Michigan in the 80’s and 90’s probably took Biochemistry 411. It was a unique class, that used the Keller Plan, an early experiment in flipped classrooms. Professor Robert Beyer created a course book which laid out explicitly what the expectations were for each of 15 modules. Students would study on their own until they understood the expectations and then take a test demonstrating mastery of the material. If they had questions they could work with student proctors to get the answers.

It was an awesome class, it was the only A+ I ever received. The class was essential med school prep because it taught me how much crap I could stuff into short term memory for a test. You can see an overview of the class Dr. Beyers wrote for an education journal here.

Dr. Beyer offered optional lecture sessions if you wanted to learn additional ancillary information and I went to a few of them. He did an awesome lecture on the benign medical nature of marajuana. He did a lecture on the importance of free radical scavengers (he was a huge Linus Pauling fan, who he called the great brain). Here is some lay press  on some of his research on free radicals. And he had a few pet molecules that he loved, one was Co-enzyme Q10. I knew more about Co-Enzyme Q than I ever thought I would need and I was pleasantly surprised to see it pop back up as a relevant medical drug twenty years later.

Another pet molecule (or I guess, element in this case) was selenium, he gave a convincing lecture that increased selenium was the key to preventing cancer. This has not worked out so well. The Select trial randomized 35,000 men to placebo, vitamin E, selenium or both vitamin E and selenium. The lowest prostate cancer rate was with placebo. Sorry Dr. Beyer.

The Journal of National Cancer Institute this week released a nested case control analysis of the same data and found that selenium and vitamin E increased the risk of prostate cancer by 90% in some patients.

Sure, take a vitamin a day, how could it hurt (besides doubling your risk of prostate cancer) http://t.co/gQCNr1YmyF H/t @drarcox
— Joel Topf (@kidney_boy) February 23, 2014

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#DreamRCT late entry: FHN Do Over

Jason Prosek has submitted another DreamRCT. Jason is an assistant professor of nephrology at the Wexner Medical Center at the Ohio State University.  He is a general nephrologist with particular clinical interests in onco-nephrology and heart failure / ultrafiltration.  He is also heavily involved in fellow education.

Jason’s RCT is trying to actually put Tessin’s hemodialysis strategy to the test. It is an interesting trial and an ambitious idea. Check it out on Medium.

Jason can be found on Twitter.

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#DreamRCT Phase 2

For the past few weeks a few contributors have posted their personal ideas about the biggest

questions in nephrology. These ideas were presented in the form of proposed randomized controlled trials. Here is the cohort of #DreamRCTs so far:

I am grateful to each one of them that took up the call and contributed to this endeavor. For their time each one has received a DreamRCT mug or t-shirt.

I’m on the Dream Team #dreamRCT pic.twitter.com/Bh0wDI9KNP
— Pascale Lane (@PHLane) February 18, 2014

Dream it. Do it. My #DreamRCT in Nephrology, & hot tea from my new favorite mug! Thanks, Joel! @kidney_boy pic.twitter.com/c0n8VQp9LR
— ⓔⓓ ⓔⓛ ⓢⓐⓨⓔⓓ (@iApothecary) February 15, 2014

UKidney has collected all of the ideas and listed them together for the community to rank these ideas. But additionally, and importantly, they have provided a mechanism for everyone to contribute their own ideas for a DreamRCT. Go to the site, check it out and contribute. Nephrology is full of dark neglected corners that could use the bright light of a well conceived, randomized controlled trial.
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#DreamRCT: Prevent DeaDD

Swapnil Hiremath, a nephrologist from the great white north has taken up the call and has submitted the sixth #DreamRCT. I met Swapnil on Twitter where he is quite clever and insightful about nephrology research. Swapnil works in Ottawa, which is apparently Canada’s capital.

He writes, “In Ottawa, we are not fazed with the polar vortex – in fact our annual winter festival, the Winterlude is going on now.” He is a true citizen of the world who made it to Ottawa from Mumbai, where he trained at King Edward Memorial Hospital. After Mumbai he proceeded to Boston to pick up an MPH from Harvard. He is currently an Assistant Professor in the faculty of Medicine at the University of Ottawa. His turn-ons are epidemiological studies in acute kidney injury, resistant hypertension and vascular access. See his citations at Google Scholar.

His DreamRCT takes a swap at the high rate of CV death in dialysis patients by randomizing ICDs to them. Clever and important idea. I love that he didn’t dream small and took a shot at one of the most important issues in dialysis. His post is hosted at Medium. Read it here.

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#DreamRCT update: PHLane comes through

That was fast, moments after posting my plea for more entries, Pascale Lane posted her entry:

O My

Andin the grand tradition of big science, she already has the follow-up study planned before unrolling patient 1 in the first study. I can’t wait for NOMAD. Read it. Great work.

Her T-Shirt is in the mail.
You could be next.
Get’em done. Post’em up.

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#DreamRCT deadline approaches

We want to open the voting for the DreamRCT a week from tomorrow, but we are running into an obvious problem, we only have 4 entries which seems a little light:

  1. The Uric Acid causes CKD RCT that I did
  2. The Phosphate trial that Jordan did
  3. The IMAGINE trial by Paul Phelan at the Renal Fellow Network
  4. PHANTOM-1 trial of anticoagulation in ESRD by Ed El Sayed

Every nephrologist I know complains about the woeful state of evidence in nephrology, but in my mind if you can’t come up with a a DreamRCT, you have no legs to stand on.

Please write it up because if we don’t get it done Jordan has all kinds of Plan B’s that I don’t want to consider.

To sweeten the deal, we have DreamRCT t-shirts. The next six people to post their dream RCT will get a T-shirt complements of yours truly. Time to raid my wallet. Write your damn DreamRCT already.


What? You say you don’t have a blog to publish it? 
No problem, I’ll host it here at PBFluids. 

What? You say you would never post it to PBFluids, because Joel was once a dick on Twitter?
No problem, tweet at Jordan Weinstein (@UKidney) I’m sure you two can work something out, or go post it to Medium.

What? You say you have enough T-shirts?
No problem, I’ll send you a mug instead.


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#DreamRCT: Anticoagulation in Hemodialysis

Back in December, I had Ed El Sayed (@iApothecary) do the first guest post on PBFluids. He wrote about Nephron D for the top nephrology stories of the year project. It was one of my most popular stories of the fourth quarter of 2013. Ed is back with his contribution to the DreamRCT project:

When should dialysis patients with non-valvular Atrial Fibrillation be anti- coagulated?

Introduction

End Stage Renal Disease (ESRD) patients on dialysis have an increased risk for bleeding due to a number of factors, most notably failure of uremic platelets dysfunction (decreased degranulation and aggregation). This increases the risk of therapeutic anticoagulation in dialysis patients, they just have a significantly increased risk of bleeding.


Quantifying this risk is important because in numerous clinical situations the choice to anti coagulate or not to anti coagulate must ejudicated. Often times, clinicians are faced with an issue where the evidence base simply does not exist, or is unfortunately, ambiguous. When trying to determine if anticoagulation for atrial fibrillation is appropriate in ESRD patients, nephrologists, cardiologists, and pharmacologists cannot mine the medical literature for an answer. The evidence is insufficient.

That being said, experts recommend anti-coagulation pharmacotherapy in ESRD patients who have one or more of the following conditions: 
  • Pulmonary Embolism
  • Deep Vein Thromboembolism
  • Anti-Phospholipid Syndrome
  • Mechanical prosthetic cardiac valve

This expert recommendation is based on the hope that the anti-coagulation benefits in those conditions outweighs the risk of bleeding.

So where do we stand?

The Dialysis Outcomes And Practice Pattern Study (DOPPS) trial and the United Stats Renal Data Service (USRDS) both demonstrated an increasing rate of atrial fibrillation (AF) among dialysis patients. AF was also shown to be more prevalent in pre-dialysis CKD patients in the Chronic Renal Insufficiency Cohort (CIRC) trial. Even more worrisome is data showing that AF in ESRD patients increases all cause mortality. On the other hand, the data is inconsistent on the association between AF and stroke in ESRD patients (no association: here, and here, positive association: previous KI article).

Another dilemma clinicians often face in clinical practice is whether to use the CHAD2S2 score to assess the need for using warfarin to prevent stroke in AF patients on dialysis. While the CHAD2S2 score is a derivative of CHADS2 score, its validity was based on data from non-renal patients and experts advocate against using it on renal patents.
Several studies have been performed to determine the benefit of warfarin in AF patients on dialysis. The results however, were inconsistent. A few studies were pro-warfarin, while others were anti-warfarin.
Despite numerous studies, prospective data is both scant and contradictory. The data in patients without renal insufficiency, while compelling cannot be used to judge the safety and efficacy of anticoagulation in dialysis. This means we do not have the data to make the decisions we need.

My Dream RCT: The PHANTOM-1 Study

Placebo in Hemodialysis vs ANTicoagulation. My aim is to design a multi-center, randomized, double blinded, placebo controlled trial to study the effect of Warfarin pharmacotherapy in AF patients who require hemodialysis. PHANTOM-1 study would have the following criteria:

  • Inclusion Criteria
    • Age range 50 – 84 years
    • Sex males and females
    • CHADS2 Score greater than or equal to 2
    • History of Non-Valvular AF for 2 or more years
    • On Warfarin with INR 2-3
    • Ethnicity White, Asian, African American
    • History of ESRD requiring hemodialysis 3 or more times weekly
  • Exclusion Criteria
    • Age range younger than 50 years and older than 84 years
    • CHADS2 Score less than 2
    • AF secondary to valvular disease
    • History of Non-Valvular AF for less than 2 years
    • On Warfarin with INR below 2 or above 3
    • Renal disease without the need for hemodialysis
    • ESRD patients undergoing Peritoneal Dialysis
    • History of Neuro-endocrine disease

The study design would have 2 arms, with one group continuing to receive oral warfarin 5-10 mg once daily to maintain INR between 2-3, while the other group receive a placebo. The outcomes of the study would be as follows:

  • Primary Endpoint – Onset of Transient Ischemic Attack (TIA) or stroke (Ischemic or Hemorrhagic)
  • Secondary Endpoint – Incident of major bleeding (outside the CNS) and access survival.

All patients in the trial would receive multi-disciplinary medical counseling and monitoring throughout the study time frame. The result of the study would be welcomed and published, regardless of the outcome.


Prospectively studying this in a randomized, placebo controlled trial would definitively answer an increasingly common question that nephrologists, cardiologists and primary care doctors face.


Update 

I received this feedback:

As a long time hematologist with an interest in anticoagulation I was very interested by your post as this is something my nephrology colleagues and I discuss all the time. I would also advocate enrolling folks not currently on anticoagulation because even in the non-dialysis population a lot of patients with afib who should be on warfarin are not. The other issues is would renal dose adjusted new direct oral anticoagulants be safer (50% Risk reduction of ICH in trials) esp when the antidote become available.
if this program gets rolling let me know how I can help.
–tom Thomas DeLoughery, MD FACP FAWMInterim Associate Division HeadProfessor of Medicine, Pathology and PediatricsOregon Health & Sciences University

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hypokalemia and metabolic alkalosis

A few years ago I was talking one of my mentors at Kidney Week, John Asplin. He mentioned

that he taught an integrated lecture on metabolic alkalosis and hypokalemia. I thought this was an inspired idea.

Teaching separate classes on both subjects results in a lot of overlap because the renal mechanisms for both disease are the same, this means that many of the diseases that cause one, also cause the other.

Additionally hypokalemia can cause metabolic alkalosis and metabolic alkalosis can cause hypokalemia, so it makes sense to teach both of these conditions in an integrated lecture.

Lastly, teaching each electrolyte individually in isolation from each other is a missed opportunity. One can only appreciate the beauty of electrolyte physiology when one understands how each electrolyte fits together and how abnormalities in one is associated and affects all of the other electrolytes.

Unfortunately, I botched the lecture. I gave this lecture for the first time for the Oakland University Beaumont Medical School this past August. I knew it didn’t go too well, but this week I received the class feedback. Overall my statistical evaluations were excellent but when I read the comments the students were jackals. They savaged this lecture.

Timing was on my side, I was scheduled to give this lecture the day after I received feedback. I’m not done tweaking it but what I did for my Tuesday lecture was add more connective tissue between the concepts, and fill in with some additional summary slides.

Right now, I’m using it as a lecture to follow-up my potassium lecture, but at OU the students didn’t have any baseline potassium knowledge. In order for this lecture to work the students must already understand the basics of potassium, especially the central role that renal potassium handling has in potassium homeostasis. Hopefully I will be able to negotiate another hour into the GU schedule for this lecture.

My next plans for this lecture is to cut out a lot of the opening slides. The purpose of those slides is to quickly move from introducing potassium and hypokalemia to getting to the truth that hypokalemia is almost solely a disease of increased renal losses.

I want to add a slide about disease opposites:

  • Pseodohypoaldosteronism type 1 and Liddle syndrome
  • Godon’s syndrome and gittleman’s syndrome
  • Adrenal insufficiency and AME

I want to add some slides on how hypokalemia causes (specifically, maintanes) metabolic alkalosis and then how metabolic alkalosis causes hypokalemia.

Here is the lecture (Keynote version | PDF)

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#DreamRCT: Prove the uric acid-CKD connection and win Richard Johnson a Nobel

Okay nephrologists, we have suffered the slings and arrows of outrageous trial after trial going

against us. It is time to put down those depressing journals full of non-significant P values and stretch our imagination. It is time to design our own dream randomized controlled trial. The assignment is to target the most important question you see in nephrology today and design a trial to answer it. One question not enough for you? Design a trial to answer two questions ACCORD style, two questions not enough, go all AASK and design a 2×3 factorial design. Money no object, forget about pesky IRBs, let your mind free and create the trial which will meaningfully push back the walls of knowledge.

After you post your entry at your site of choice, UKidney will host a summary with a link for each entry and gather votes for the best. You can take a look at Jordan Weinstein’s Dream RCT here.

And may the IRB be ever in your favor.

My Dream RCT: Background

Humans have higher uric acid levels than almost other animals. This is primarily due to the lack of uricase, but also due to our efficient renal reabsorption of filtered uric acid by URAT1 and GLUT9. Traditionally, it has been believed that hyperuricemia causes renal disease by precipitating intraluminal crystals, analogous to gout crystals in the joints. More recent data however, implicates lower levels of uric acid in hypertension and chronic kidney disease through suppression of nitric oxide formation, stimulation of inflammation through NF-kappa beta and other mechanisms. Supporting these theories are animal studies that show febuxostat and allopurinol reduce renal damage in multiple models of kidney disease (here and here).

Epidemiologic studies linking uric acid to chronic kidney disease show a definite association but whether the uric acid causes the kidney disease is difficult to tease out. Attempts to show that have shown mixed results.

Four interventional studies have attempted to answer this question in humans:

  • Siu et al. randomized 54 hyperuricemic patients to placebo or enough allopurinol to normalize the hyperuricemia. After a year there was less creatinine progression with the allopurinol.
  • Goicoechea et al. randomized 113 hyperuricemic patients to no therapy or 100 mg of allopurinol for two years. They found improved renal function with drug compared to modest loss of function without allopurinol. And intriguingly they also found a significant reduction in cardiovascular events.
  • Shi et al. evaluated 40 patients with IgA nephropathy for 6 months. This was a negative study with no effect on GFR (but that is hardly surprising given the very short follow-up time), but it did have a beneficial effect on hypertension
  • Momeni et al. performed a 4 month double blind, placebo controlled trial of type 2 diabetics and found a reduction in proteinuria.

From Goicoechea’s study of 100 patients

More information can be found on uric acid in my grand-rounds or in an excellent Narrative Review from AJKD.

Despite multiple randomized trials showing allopurinol to be effective in CKD, don’t be fooled, both trials were tiny with limited follow-up.

Diameter of the circle is proportional to the trial size

Given that background, it seems well past time to commit to finding a definitive answer to the question of whether we should be using xanthine oxidase inhibitors to slow the progression of chronic kidneys disease.

Scouring ClincalTrials.gov I could find only one study that is addressing this hole in our knowledge. The Joslen Center is planning, but has not yet started enrolling, a double-blind, placebo controlled multi-center trial of allopurinol in type 1 diabetics. The study design looks pretty sharp with iothalamate GFRs after 3 yrs of therapy being the primary outcome. However I am dreaming bigger and want my study to apply to all patients, not just type 1 diabetics with nephropathy.

My Dream RCT: methods

My dream study is a placebo controlled, double-blind, multi-center, randomized controlled trial. The study population is CKD stage 3 patients with hyperuricemia (uric acid over 7 mg/dL). This represents a lot of the population with kidney disease which means that the results, if positive, would literally influence the treatment of millions of people. The study will use block randomization and quotas to assure a varied distribution of renal disease. At least a third of the population will have proteinuria and half will have diabetes.

All patients with proteinuria would need to be on RAAS inhibition unless they could not tolerate it. Blood pressure would be treated by the treating physician using JNC8 guidelines. Patients would be randomized to one of three arms:

  • placebo
  • allopurinol 100 mg daily
  • fubuxostat 40 mg daily

If the uric acid remained above 7 after one month of treatment the study drug would be doubled. Patients intolerant to the assigned drug could cross over to the other study drug. Study coordinators would signal a central dispensary that patients were intolerant and the dispensary would change patients on placebo to another placebo (essentially no change at all) and patients on one of the xanthine oxidase inhibitors would cross over to the other xanthine oxidase inhibitor. By employing this three arm approach we will be able to assess if any affects is due to a specific xanthine oxidase inhibitor or a more general effect of lowering the uric acid. It will also allow us to get detailed data on the tolerability and safety of the drugs in CKD.

The primary end-point is a composite of doubling of serum creatinine, death or dialysis.

Secondary endpoints are achieved ambulatory blood pressures, hospitalizations, new cardiovascular events, and gout.

This study would have results applicable to the millions of people with chronic kidney disease and would open up the first novel front in the war on CKD since the wide use of RAAS inhibition.

UPDATE
Apparently this RCT is not a dream but a trial that is going to be done, from Swapnil Hiremath:

.1/2 @kidney_boy Joel, I thought you knew about the ongoing CKD FIX trial down under: https://t.co/DnG4BHu5vp Allopurinol 100-300 mg …
— swapnil hiremath (@hswapnil) January 29, 2014

2/2 @kidney_boy gr8 It’s in CKD patients, n 620, with change in GFR as 1 outcome.
— swapnil hiremath (@hswapnil) January 29, 2014

Looking through the registry data the CKD-FIX trial sounds like a pretty close match to my Dream RCT, my one concern is they were supposed to begin enrolling patients in March of 2012 but have yet to enroll they”re first patient (according to the registry). Anyone know if this study is still going to happen?

UPDATE 2
It is on. CKD-FIX to start enrolling next month.

. @kidney_boy confirmed : CKD – FIX recruitment set to begin in Feb 2014, starting in Brisbane
— swapnil hiremath (@hswapnil) January 31, 2014