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)

#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.

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?

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 difference between treatment and prevention

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.

Fix Kidney Wikipedia #fikiWiki

Nephrology is a specialty in crisis. Fewer and fewer internal medicine residents are looking toward nephrology as a viable career. 

In 2011 there were 1.27 applicants for every nephrology fellowship position. In 2013 there were 0.76. http://t.co/3w6C7Cgd9j
— Joel Topf (@kidney_boy) January 9, 2014

The number of applicants continues to plummet. A number of people are looking at ways to increase interest. I’d like to point you to Mark Parker’s work with the ASN and Tejas Desai’s essay for F1000 (comments on the article). 
One of the solutions that people repeatedly return to is the need for better nephrology mentors for medical students and residents. I, like most people who ultimatly pursued nephrology can point to a great mentor. During my fourth year of medical school, I rotated with Dr Shermine Dabbagh, a pediatric nephrologist at children’s hospital of michigan. She was a great teacher and a caring clinician, but she was not my primary influence.
The chief inspiration was not a person at all, it was a book. During my fourth year of medical school, years before I was ready, I read Burton Rose’s classic, Clinical Physiology of Acid-Base and Electrolyte Disorders. It is a wonderful book and it absolutely was the inspiration that launched my career.
While the ASN is working on improving mentors, I think the influence of supportive texts like Rose’s should not be ignored. There are still great nephrology texts, but unfortunately students no longer use textbooks. They use the web and are increasingly depending on Wikipedia. Unfortunately the Kidney Wikipedia is pretty run down. It doesn’t give a reader the impression that the specialty is vibrant, well kept and alive.

Wikipedia is increasingly becoming the initial access point for people to learn about nephrology and we should be better caretakers of it as it is a reflection of our specialty.

I think a great way to revitalize student impression of nephrology is to fix the kidney Wikipedia.
FIx the KIdney WIKIpedia.
Academics scoff at wikipedia, but it will be easier to fix wikipedia than it will be to get a generation of medstudents and residents to stop using it. It is time to stop fighting the Wikipedia and instead we should start refining it, fill it with compelling content that shows off nephrology as the exciting, important and a field that embraces the future of medical education. 
For more information on my opinions about wikipedia check out my editorial at Wing of Zock.

How I learned to stop fearing and love Wikipedia….my latest editorial at Wing of Zock. Go read it: http://t.co/ulIC823p30
— Joel Topf (@kidney_boy) January 23, 2014

@kidney_boy Nice article, biggest limitation is getting trainees to recognize errors? (especially subtly incorrect info)?
— DrWario (@DoctorWari0) January 23, 2014

@DoctorWari0 but isn’t that 1 of the most important lessons we should be treating students, how to recognize when source material is correct
— Joel Topf (@kidney_boy) January 24, 2014

@kidney_boy Loved your write up on @Wikipedia for @wingofzock potential exercise for #flippedlearning: use class time to edit wiki
— Rob Cooney, MD, MEd (@EMEducation) January 23, 2014

@kidney_boy @ShabbirHossain @krw127 We’re all “guilty”(?) of using wikipedia. knowing the limits of your sources is important. Thx for post!
— Charlie M. Wray (@WrayCharles) January 24, 2014

Yep. Also, Wikipedia is a good starting point MT @kidney_boy: How I learned to stop fearing and love Wikipedia…. http://t.co/OxXYzQUgRk
— Miloš Miljković (@Miljko) January 23, 2014

Twitter, Nephrology and the next version of the KDIGOmobile App

This summer, through luck and/or moxie I was able to land a plum position on the KDIGO team charged with building the mobile app. The team partnered with the crazy effective nerds at Visible Health to push out our initial vision. Our 1.0 for iPad was launched at ASN Kidney Week in Atlanta. Internally, we described the project as building a bridge across a gorge. This 1.0 is like a piece of dental floss connecting the two sides. It is an important step but it we have big plans for future versions.

We have received a lot of feedback on the initial release and the overwhelming requests are: Android, iPhone, Android, iPhone, Android, iPhone.

We are going to do both, but neither are the next step. The 1.0 version is essentially a PDF reader with all 9 KDIGO guidelines pre-loaded. Moving the app to Android and the iPhone will entail porting all of the guidelines to a new data model. We have a big vision for the product and are reworking the infrastructure to get there. Those two updates will come but they need to wait for the new data structure, for now, the only thing I can tell you is: Patience.

The current version of KDIGO Mobile has a community option that is a ghost town. We are going to tear that down and instead adopt the renal community on Twitter. The new social section will have a number of ways to view twitter that are designed to expose new people to the vibrant nephrology discussions that occur in there.

Users will have a number of twitter channels that they can tune into:

  • Current Twitter users will be able to view their timeline
  • Collecting duct: this is a highly selected list of twitter accounts consisting primarily of professional societies, journals and government organizations (Members | Timeline)
  • Proximal tubule: this is a highly curated list of users that typically provide intelligent nephro-oriented discussion  (Members | Timeline)
  • Glomerulus: this is a general list of every nephrologist and nephrology related organization I could find. (Members | Timeline)
  • Hashtags: this will be one or two hashtags that are of interest to nephrologists. For example, during next years Kidney Week, we would push out #KidneyWk14, during NephMadness we would highlight #NephMadness, We might leave #MedEd, #FOAMed, and #HCSM up at other times. etc.

All of these channels are stored on the servers at Visible Health so they can be controlled remotely and are eternally updatable.

Today, we are asking members of the nephrology social media sphere to look at the lists, try out the timelines, explore the hashtags. Tell us if we missed anyone or added someone undeserving.

When evaluating the timelines keep in mind the goal of these Twitter channels. We want to introduce new users to the utility of twitter for nephrology discussions. The timeline that I am most concerned about is the proximal tubule. The collecting tubule is an official channel and will likely be pretty dry. The glomerulus I think will be too much of a fire hydrant and I am thinking about dropping that channel altogether. I’m hoping that the proximal tubule can have relevant, compelling, content to really show off the utility of Twitter to naive KDIGO users.

Any and all feedback would be appreciated.


SYMPLICITY-3 was Medtronic’s play to get into the hypertension business. They have a device that allows physicians to apply burn the sympathetic nerves of the renal arteries and lower the blood pressure. In a previous randomized trial it worked and SYMPLICITY-3 was what they were going to take to the FDA to get approval.

I started the day with our local hypertension guru explaining the inclusion criteria for Symplicity-4. An hour later this hit the wire:

Full press release

I was a huge fan of renal denervation and a bit of me died when the tweets started flying. Our local Symplicity PI says that the follow-up study with looser enrollment criteria, SYMPLICITY-4, has been cancelled. MedTronic supposedly is still going to carryout a trial of renal artery sympathetic nerve ablation in heart failure. If that is positive then it is possible the field will carry on, but if they abandon that, it may be lights out for the entire concept.

First CORAL, now SYMPLICITY 3. It’s been a bad couple of months for the renal arteries. They should get a better PR person.
— Joel Topf (@kidney_boy) January 9, 2014

Some thoughts on simplicity 3. The trial was on patients with severe resistant hypertension: office blood pressure over 160 on three blood pressure medications. These are hardcore hypertensives. This may not be an appropriate crucible to test the hypothesis of weather this works.

Thought two is that sympathetic discharge is thought to drive a lot of the hypertension in CKD and ESRD. (See this, this, and most importantly this editorial review)  So maybe when SYMPLICITY-3 excluded patients with GFR’s less than 45 they were excluding the very patients where the treatment would be most effective.
Thought three is that maybe in an effort to increase enrollment there were more inexperienced doctors doing the ablation. Unlike renal artery and coronary artery stenting there is no convenient sympathetic nerve ablation analog to TIMI-3 flow. At the end of the procedure the team has no idea if they successfully and adequately ablated the nerves. This could be a confounder. 
It will be interesting in subgroup analysis pif they find a signal pointing to efficacy being related to operator experience or a signal to better efficacy with worse GFR.
I blogged about SYMPLICITY here. Here is what Renal Fellow Network wrote about renal denervation when it was one of the top stories on 2010 and in an insightful post by Matt Sparks

Fluid and Electrolyte Curriculum for Residency

I give monthly lectures to the residents at three hospitals. I bill the lectures as a comprehensive, year-long, fluid and electrolyte course. I have never established a fixed curriculum for the lectures, here is one take:

  1. Body water, IV fluids and diuretics
  2. Rapid interpretation of ABGs
  3. Acute Kidney Injury
  4. Osmoregulation and hyponatremia
  5. Hypernatremia
  6. Anion Gap metabolic acidosis
  7. Potassium
  8. Metabolic alkalosis and hypokalemia
  9. Non-anion gap metabolic acidosis
  10. Calcium and phosphorous and metabolic bone disease
  11. Electrolyte emergencies
  12. Board review practice
The curriculum starts with the basic mechanics that interns need to function in the hospital. How to order IVs, and intelligently use diuretics. This includes a review of body fluid compartments so that it is not just practical pearls but is based on physiologic foundation.
Electrolyte emergencies is a lecture that is not entirely written and needs to be. It would be a practical handbook style lecture to walk interns and residents through what I think is the best way to handle: metabolic acidosis and alkalosis, hypo- and hypernatremia, hypo- and hyperkalemia, hypo- and hypermagnasemia, hypo- and  hypercalcemia.
The introductory curriculum ends with the rapid interpretation of ABGs. After that I turn the intensity up a bit and focus on more physiologic based and less practical aspects of electrolytes. This allows deep dives on metabolic acidosis with separate lectures on anion and non-anion gap. I separate out metabolic alkalosis and potassium to provide time to do a deep dive on the monogenic causes of hypertension.
The board review session is a quiz session to review all the concepts of the year.
I have one spare month because a lecture always gets lost along the way.

Kidney TREKS deadline approaches

Kidney TREKS is a program for medical students who want to learn about nephrology. Here are the components of the program from the website:

  • Attend the Mount Desert Island Biologic Laboratories “Origins of Renal Physiology” course for students, June 6-13, 2014. Tuition, travel stipend to Maine, room and board are paid by ASN.
  • Become connected with a nephrologist-mentor who will interact with the student over the course of medical school training, graduate school or postdoctoral fellowship.
  • Attend ASN Kidney Week during the 3rd or 4th year of medical school or graduate school with travel support (as a part of the ASN Program for Students and Residents).
  • Receive complimentary membership to the ASN with access to website resources for students.

To my mind, the first bullet point stands out as a once in a life-time opportunity. Mount Desert Island (by the way, best name ever: it’s a mountain, and a desert, and an island. Too bad they couldn’t get swamp and archipelago in there somehow) is a research lab where some of the seminal discoveries of renal physiology were made. My understanding is that the students have an opportunity to re-run some of the classic experiments with scientist mentors. Imagine a whole week of Kidney Science Camp.
I have not seen any reviews from participants from last year’s KidneyTreks but the reports from the fellow version make me want to re-do fellowship so I can go.
The deadline for applications is January 24th. Get to the link and apply now.
Imagine hiking around this beautiful island after learning the secretes of glomerular filtration.
Mount Desert Island Biologic Lab, home to the world’s nerdiest fence.