musings of a salt whisperer
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.
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’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
In the past I have posted my Apple predictions on PBFluids, but I am going to keep this blog kidney focussed, so I posted my 2014 Apple Predictions on Medium, a fantastic blogging platform if anyone is looking to start writing online.
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.
That was fast, moments after posting my plea for more entries, Pascale Lane posted her entry:
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.
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:
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.
This expert recommendation is based on the hope that the anti-coagulation benefits in those conditions outweighs the risk of bleeding.
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
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:
I want to add some slides on how hypokalemia causes (specifically, maintanes) metabolic alkalosis and then how metabolic alkalosis causes hypokalemia.
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.
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:
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| 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 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:
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
The second twitter journal club a classic article by Rose, Strategy of prevention: lessons from cardiovascular disease. Br Med J 1981 282 pp. 1847-51.
My favorite line:
When ordinary doctors do not accept that responsibility then prevention is taken over (if at all) by uncritical propagandists, by cranks, and by battling commercial interests.
And this, on the treatment of hypertension:
A general practitioner, say, makes a routine measurement of a man’s blood pressure and finds it raised. There after both the man and the doctor will say that he “suffers” from high blood pressure. He walked in a healthy man but he walks out a patient, and his new-found status is confirmed by the giving and receiving of tablets. An inappropriate label has been accepted because both public and profession feel that if the man were not a patient the doctor would have no business treating him. In reality the care of the symptomless hypertensive person is preventive medicine, not therapeutics.
A systolic pressure of 160mm Hg may be common at these ages, but common does not mean good.
Remids me of this post from the archives.