musings of a salt whisperer
The ASN Kidney Week podcast day three has low volume levels and a lot of background noise. This is easy to correct. I ran the podcast through Auphonic, which is free and got a huge improvement.
You can listen to the improved podcast here:
and here is the original for comparison
My attitude toward the supplement has been a journey.
I am now converted and I pray at the Alter of the Supplement. However, as a private practice nephrologist, working on the edge of the academy, getting access to manuscripts means that I have always depended on the kindness of strangers (actually usually less strangers and more friends, but one never pass up an opportunity to drop a Blanche DuBois quote). Using this beg-borrow-steal system means I almost always end up with the the manuscript sans supplement. Why do journals have separate downloads for the manuscript and supplement? Contemporary manuscripts regularly reference a table or figure from the supplement so you can’t even understand the manuscript without the supplement. I can get behind requiring a separate download for super specialized information like a protocol, or raw data tables, but most of the content of a typical supplement should ride with the core manuscript and not be a separate download.
A casualty of the tyranny of the page and figure count is the consort diagram. The consort diagram used to be the traditional figure 1, but it is now regularly banished to the supplement. We should not allow rules designed to minimize shipping costs determine the length and completeness of our scientific manuscripts. We need to embrace the reality of frictionless distribution and throw away print-inspired word and figure limits and provide all of the relevant information and data in the manuscript itself (or in a supplement that is part of the download package.
Here was my most recent tweet of this idea:
I guess this has bubbling in my head for a few years now
Josh Farkas is also steadfast in his conspiracy explanation
two years ago:
and here is his reply to my latest tweet on the topic
Nephrologists and calculators go together like Captain Kirk and his communicator.
We all have our favorites and work flows get cemented around these favorites. My favorite calculator for eGFR and the Kidney Failure Risk Equation is Stephen Fadem’s MDRD.com. It isn’t pretty but it is amazingly functional. It reminds me of how Neal Stephenson describes the power of Unix by telling a story of a drill in the essay In the Beginning was the Command Line (which amazingly enough is available, in its entirety, on a single web page at Stanford.edu). I am including it here
THE HOLE HAWG OF OPERATING SYSTEMS
Unix has always lurked provocatively in the background of the operating system wars, like the Russian Army. Most people know it only by reputation, and its reputation, as the Dilbert cartoon suggests, is mixed. But everyone seems to agree that if it could only get its act together and stop surrendering vast tracts of rich agricultural land and hundreds of thousands of prisoners of war to the onrushing invaders, it could stomp them (and all other opposition) flat.
It is difficult to explain how Unix has earned this respect without going into mind-smashing technical detail. Perhaps the gist of it can be explained by telling a story about drills.
The Hole Hawg is a drill made by the Milwaukee Tool Company. If you look in a typical hardware store you may find smaller Milwaukee drills but not the Hole Hawg, which is too powerful and too expensive for homeowners. The Hole Hawg does not have the pistol-like design of a cheap homeowner's drill. It is a cube of solid metal with a handle sticking out of one face and a chuck mounted in another. The cube contains a disconcertingly potent electric motor. You can hold the handle and operate the trigger with your index finger, but unless you are exceptionally strong you cannot control the weight of the Hole Hawg with one hand; it is a two-hander all the way. In order to fight off the counter-torque of the Hole Hawg you use a separate handle (provided), which you screw into one side of the iron cube or the other depending on whether you are using your left or right hand to operate the trigger. This handle is not a sleek, ergonomically designed item as it would be in a homeowner's drill. It is simply a foot-long chunk of regular galvanized pipe, threaded on one end, with a black rubber handle on the other. If you lose it, you just go to the local plumbing supply store and buy another chunk of pipe.
During the Eighties I did some construction work. One day, another worker leaned a ladder against the outside of the building that we were putting up, climbed up to the second-story level, and used the Hole Hawg to drill a hole through the exterior wall. At some point, the drill bit caught in the wall. The Hole Hawg, following its one and only imperative, kept going. It spun the worker's body around like a rag doll, causing him to knock his own ladder down. Fortunately he kept his grip on the Hole Hawg, which remained lodged in the wall, and he simply dangled from it and shouted for help until someone came along and reinstated the ladder.
I myself used a Hole Hawg to drill many holes through studs, which it did as a blender chops cabbage. I also used it to cut a few six-inch-diameter holes through an old lath-and-plaster ceiling. I chucked in a new hole saw, went up to the second story, reached down between the newly installed floor joists, and began to cut through the first-floor ceiling below. Where my homeowner's drill had labored and whined to spin the huge bit around, and had stalled at the slightest obstruction, the Hole Hawg rotated with the stupid consistency of a spinning planet. When the hole saw seized up, the Hole Hawg spun itself and me around, and crushed one of my hands between the steel pipe handle and a joist, producing a few lacerations, each surrounded by a wide corona of deeply bruised flesh. It also bent the hole saw itself, though not so badly that I couldn't use it. After a few such run-ins, when I got ready to use the Hole Hawg my heart actually began to pound with atavistic terror.
But I never blamed the Hole Hawg; I blamed myself. The Hole Hawg is dangerous because it does exactly what you tell it to. It is not bound by the physical limitations that are inherent in a cheap drill, and neither is it limited by safety interlocks that might be built into a homeowner's product by a liability-conscious manufacturer. The danger lies not in the machine itself but in the user's failure to envision the full consequences of the instructions he gives to it.
A smaller tool is dangerous too, but for a completely different reason: it tries to do what you tell it to, and fails in some way that is unpredictable and almost always undesirable. But the Hole Hawg is like the genie of the ancient fairy tales, who carries out his master's instructions literally and precisely and with unlimited power, often with disastrous, unforeseen consequences.
Pre-Hole Hawg, I used to examine the drill selection in hardware stores with what I thought was a judicious eye, scorning the smaller low-end models and hefting the big expensive ones appreciatively, wishing I could afford one of them babies. Now I view them all with such contempt that I do not even consider them to be real drills--merely scaled-up toys designed to exploit the self-delusional tendencies of soft-handed homeowners who want to believe that they have purchased an actual tool. Their plastic casings, carefully designed and focus-group-tested to convey a feeling of solidity and power, seem disgustingly flimsy and cheap to me, and I am ashamed that I was ever bamboozled into buying such knicknacks.
It is not hard to imagine what the world would look like to someone who had been raised by contractors and who had never used any drill other than a Hole Hawg. Such a person, presented with the best and most expensive hardware-store drill, would not even recognize it as such. He might instead misidentify it as a child's toy, or some kind of motorized screwdriver. If a salesperson or a deluded homeowner referred to it as a drill, he would laugh and tell them that they were mistaken--they simply had their terminology wrong. His interlocutor would go away irritated, and probably feeling rather defensive about his basement full of cheap, dangerous, flashy, colorful tools.
Unix is the Hole Hawg of operating systems, and Unix hackers, like Doug Barnes and the guy in the Dilbert cartoon and many of the other people who populate Silicon Valley, are like contractor's sons who grew up using only Hole Hawgs. They might use Apple/Microsoft OSes to write letters, play video games, or balance their checkbooks, but they cannot really bring themselves to take these operating systems seriously.
I never realized how irreplaceable MDRD.com was until it went offline for a couple of weeks.
People were quick to offer suggested work arounds.
KidneyFailureRisk.com was a frequent suggestion. I love KidneyFailureRisk.com, but it is not a serious tool for my workflow. It is designed for patients and provides a clean, patient-friendly interface and provides the results in a way that encourages intervention while providing reliable, actionable information with links for further education from vetted sources. All good. But it fails me as a serious tool:
And the most important reason this page fails as a serious tool is it requires me to know the eGFR. MDRD, starts with creatinine, age, gender, and cystatin C, so it first calculates the eGFR and then the Tangri KFRE. This small innovation makes it so powerful. Love this insight into how professionals work.
The other alternative recommended was Calculate by QxMD from Medscape which is actually pretty good, the only problem is that it again requires that you know the eGFR to run the calculation.
And honestly, I don’t love that the calculator is supported by pharmaceutical advertising.
But MDRD.com is back and I am happy with my ugly, but highly efficient tool.
This week I discussed last week’s examination of the Calcifediol story.
You can see all of my newsletters here.
I’m enjoying this. It is forcing me to develop some isolated tweets into longer, hopefully, more thoughtful blog posts that then turn into newsletters.
Please subscribe.
We all are drowning in e-mail. Today I got one from Akhtar Ashfaq, Senior Vice President, Clinical R&D, and Medical Affairs Renal Division at OPKO Pharmaceuticals.
The e-mail promises that new research shows that using calcifediol to correct PTH slows the progression of chronic kidney disease. Big if true. It is not true, and this publication actually lays bare how cynical some pharma-sponsored publishing can be.
Hours after writing this I was thinking about the tweet and it hit me. If the data OPKO used to see that the drop in PTH was associated with decreased progression of CKD was from the pivotal trial they used for approval then it was a randomized, placebo-controlled, trial and that OPKO had the data that would actually answer the question. So I pulled up the methods of the manuscript to see where the data came from.
Yep, they were randomized, placebo controlled trials. The two trials were combined and published in this manuscript (Sprague, S Am J Nephrol 2016).
And the authors looked at the most important question regarding the treatment of secondary hyperparathyroidism in CKD, “Does it slow the loss of GFR?”
No. Despite a powerful effect on PTH, there was no signal that use of calcifediol made a bit difference in the loss of eGFR.
Now this study only had patients on placebo controlled medications for 26 weeks, so perhaps there was not enough time to see a difference. But this is not the only attempt to use vitamin D to preserve kidney function. The large (1300 people randomized) and long (5 years) VITAL Study included an analysis of CKD progression and found no effect on eGFR or albuminuria. (H/T Gunnar Henrik Heine)
And last year Yeung, et al did a meta analysis of vitamin D therapy in CKD and likewise found no effect on all-cause mortality (relative risk [RR], 1.04; 95% CI: 0.84, 1.24), cardiovascular death (RR, 0.73; 95% CI: 0.31, 1.71), or fractures (RR, 0.68; 95% CI: 0.37, 1.23).
Every hyponatremia consult recommends increasing protein intake to increase the solute load and increase urine output. But how much protein do you need to move the needle?
Here is another way to do the calculation
Protein is about 16% nitrogen
And urea is just under 50% nitrogen by weight
So if you are using 2 packets of urea (30 grams) a day for SIADH, you should get an equivalent amount of urinary solute (and increased urine output) with three scoops of protein powder.
For this calculation I used this protein powder which has 18 scoops for $22.
The TREASURE Study (H/T Pablo Garcia) tested 17 patients with SIADH. They were given 90 grams of protein (three scoops!) for seven days then after a washout they were given 30 grams of urea. for seven days
The results were modest, but there was little material difference between the two therapies.
Patients quality of life improved during the protein phase and fell during the urea phase
The rating for overall well-being slightly improved from 7 VAS points (6-8) to 8 VAS points (7-8) (P = .24) upon protein intake, whereas it slightly worsened from 7 VAS points (6-7) to 6 VAS points (6-7) (P = .40) upon urea intake.
Update
David Goldfarb asked about changes in bicarb with the protein supplement
So I went digging into the supplement to see if they reported it. (They did not) and I came across this humdinger
It shows patient level data on the change in Na. Strange that they didn’t mention that almost a third of patients in the in protein supplement group had their sodium fail. No failures among the urea patients (except one person with inadequate protein intake. That is the asterisk).
Animated gif to make this more clear
I’m glad this is reported. But it should not be in the supplement, it should be in the main paper.
In a related note, Roger Rodby suggests hot dog therapy.
I took Roger’s hotdog therapy and made it into an animated gif
Here are the two key slides in the build
and
Cardiology developed one the most fantastic medical technologies of the late twentieth century, the percutaneous coronary intervention. The problem that PCI tackled was obvious, patients with coronary artery disease had demonstrable arterial narrowing and we had a technique that could treat this narrowing. How could we not treat it? How could patients not benefit from this? And following these interventions patients had remarkable improvements in angina, the primary symptom of coronary disease. In addition to improving chest pain, this intervention had to prevent heart attacks and save lives. This assumption was accepted fact at the beginning of my career, however some cardiologists were unsatisfied with using intuition to guide therapy and PCI came under the sharp blade of the randomized controlled trial. COURAGE shot down the idea that providing cardiac (bare metal) stents in patients with stable coronary disease provided any survival benefit. This was repeated with ISCHEMIA (now with drug eluting stents). And then ORBITA used sham procedures to question whether PCI even reduced angina, a finding that was at least partly reversed by ORIBITA-2 which removed the use of anti-anginal medications.
This post is not intended to provide a comprehensive review of the use of PCI in coronary disease but to use it as a demonstration how an intuitive therapy that seems to have obvious and unquestioned use, can be questioned and through those qquestions we can reposition the procedure to use it where it is helpful and not waste resources and treat patients with science and not vibes.
This takes us to dialysis. Dialysis unquestionably helps some patients but I don’t think it helps all patients. Nephrology has rarely subjected dialysis to the rigors of a randomized controlled trial and this is to our patients detriment. We have little evidence to guide us as to when to offer dialysis and when not to. One area that has been extensively explored with RCTs is when to initiate dialysis in AKI, and honestly, it wasn’t pretty for dialysis.
Last week Dr. Manjula Tamura published a Target Trial Emulation of an RCT to see how survival differs between elderly patients (age over 65) with a GFR of 12 and immediately starting dialysis (average was 8 days after trial inclusion) versus delaying dialysis at least 30 days (average was 3 years after trial inclusion). The author tracked two outcomes:
The results showed that starting dialysis at 12 ml/min resulted in survival for 770 days. For the cohort who delayed dialysis survival was 761 days. The difference was non-significant.
This image is powerful
The trial was covered in the New York Times!
I am confused by Target Trial Emulation. I am suspicious that people started on dialysis at a GFR of 12 and people that go for 3 years before starting dialysis (in the delayed group) are really interchangeable. I am confused how the late start group can start dialysis an average of 3 years after inclusion in the study while only surviving an average of 761 days (2.1 years) But it is clear to me that nephrology has failed at doing studies to determine who benefits from dialysis. And I believe that old frail people do not get the benefit from dialysis that we dream of. This was shown in an earlier study by Dr. Manjula Tamura which showed dialysis to be a blood bath for nursing home patients. (Tamura, NEJM 2009). I have used this study to guide me in the advice I give patients. It is just an observational study but it showed the folly in believing that the frail patient in the nursing home will turn around as soon you clear the uremia. That’s just a fairy tale we tell ourselves. It almost never happens and the reality is that almost all of these patients are either dead or further debilitated a year later.
As Dr Tamura says in her Tweetorial about the study, it is time for randomized trials to see where dialysis helps and where it falls down. We need to have the COURAGE to test whether what is intuitively helpful actually delivers benefits. The cardiologists have used clinical trials to define the role of PCI in coronary disease, we should do the same for our patients.
Good question about a confusing topic:
In Lecture 19, it is mentioned that hypokalemia leads to decreased NaCl reabsorption in the distal convoluted tubule. I do not understand why this occurs. Dr. Topf said that when you have hypokalemia, you will have decreased Na/Cl/K activity in the TAL, which will lead to increased Na and Cl delivery distally, so shouldn’t that increase NaCl reabsorption in the DCT?
It is also mentioned in this lecture that hypokalemia stimulates H+ secretion in the PCT. I am confused why this occurs as well.
Okay, let’s take this one question at a time, and let’s do it in anatomic order starting in the proximal tubule.
In hypokalemia potassium leaks out of the cell to restore extracellular potassium. In order to maintain electroneutrality, Hydrogen ions (protons) move into the cell.
This causes intracellular acidosis. In the proximal tubule this intracellular acidosis “fools” the proximal tubule cells into thinking there is systemic acidosis and their natural response to this “acidosis” is to accelerate the movement of intracellular hydrogen into the tubule, there by increasing proximal tubule bicarbonate resorption.
Here are the relevant slides from the presentation:
Anatomically the next relevant tissue is the thick ascending limb of the loop of Henle (TAL)
Here the question is how hypokalemia affects the TAL, the TAL is powered by the Na-K-2Cl pump, decreased potassium means decreased NaK2Cl activity, so less sodium is reabsorbed and more sodium moves distally. Here is the relevant slide from the deck.
And finally to the crux of your question, “Shouldn’t that increase NaCl reabsorption in the DCT?”
YES it does!
The increased sodium reabsorption in the distal cortical collecting tubule is what drives further H and K secretion which perpetuates the metabolic alkalosis and hypokalemia!
Here is a text slide describing it followed by an animated gif of the relevant slides
I hope that helps clarify the question.
New question:
Good morning,
I hope you are well. I was looking at the explanation for this practice question that I believe is from your lectures, and I was a little confused at the explanation which describes this as a “SIADH syndrome from the patient not being able to excrete water taken in during the marathon”. Could you elaborate how you would know this is SIADH? My original thinking was that they were electrolyte depleted from the extended exercise as well as hyperglycemia, so having had an energy drink would have helped them.
My answer:
This is classic exercise induced hyponatremia.
The stress of extreme exercise (especially in people not in great physical condition) causes them to retain water via a non-osmotic release of ADH.
These patients actually gain weight during the marathon and are not electrolyte depleted.
A great study on this was published in the NEJM in 2005
Here is the abstract
Hyponatremia has emerged as an important cause of race-related death and life-threatening illness among marathon runners. We studied a cohort of marathon runners to estimate the incidence of hyponatremia and to identify the principal risk factors.
Participants in the 2002 Boston Marathon were recruited one or two days before the race. Subjects completed a survey describing demographic information and training history. After the race, runners provided a blood sample and completed a questionnaire detailing their fluid consumption and urine output during the race. Prerace and postrace weights were recorded. Multivariate regression analyses were performed to identify risk factors associated with hyponatremia.
Of 766 runners enrolled, 488 runners (64 percent) provided a usable blood sample at the finish line. Thirteen percent had hyponatremia (a serum sodium concentration of 135 mmol per liter or less); 0.6 percent had critical hyponatremia (120 mmol per liter or less). On univariate analyses, hyponatremia was associated with substantial weight gain, consumption of more than 3 liters of fluids during the race, consumption of fluids every mile, a racing time of >4:00 hours, female sex, and low body-mass index. On multivariate analysis, hyponatremia was associated with weight gain (odds ratio, 4.2; 95 percent confidence interval, 2.2 to 8.2), a racing time of >4:00 hours (odds ratio for the comparison with a time of <3:30 hours, 7.4; 95 percent confidence interval, 2.9 to 23.1), and body-mass-index extremes.
Hyponatremia occurs in a substantial fraction of nonelite marathon runners and can be severe. Considerable weight gain while running, a long racing time, and body-mass-index extremes were associated with hyponatremia, whereas female sex, composition of fluids ingested, and use of nonsteroidal antiinflammatory drugs were not.
As part of this study they looked at sport drinks versus drinking pure water and it did not affect the risk of developing hyponatremia (which was 13% of Boston Marathon runners!):
Additional adjustment for female sex (P=0.20) or drinking 100 percent water (P=0.89) was not statistically significant and did not appreciably alter the coefficients of the remaining variables in the model.
Is this clear or do you need more?
Instead of having a number of separate posts, I’m going to answer three questions here
I am a little bit overwhelmed seeing the additional 31 page document that requires memorizing several new concepts including a multi-step equation problem to calculate IV fluid orders. Would these equations be provided to us on the TBL tomorrow? Is this more of a prep for how your material will be tested on the final exam?
No need to memorize any equations, all equations that you need for the TBL will be provided to you. Same with the exam for the renal section.
I very much enjoyed your lecture on renal disorders, and wanted to clarify some confusion I had about Tea and Toast syndrome.
This is where my head is at:
Low solute load leads to decreased medullary interstitium gradient, which makes it more difficult for water to be reabsorbed (against said gradient) effectively.
This is where I need clarification:
I believe urine output is low in this condition, but I am having trouble with the cause-and-effect system, given that you said ADH is low. I am wondering if the kidneys are actively reabsorbing water to prevent excess water loss, or if they are actively trying to concentrate the urine. My assumption would be that reabsorbing more water would contribute to further hyponatremia by dilution.
Yes the kidney is unable to make the large quantity of low osmolar urine it needs to correct the hyponatremia. In most cases of hyponatremia this is because of pesky ADH, but in tea and toast ADH is appropriately suppressed. But the kidney only makes a small amount of dilute urine due to lack of solute.
Urine osmolality can only drop to a minimum of 50 mmol/l (higher in an aging or damaged kidney). So if the patient is only eating 100 mmol of solute a day (tea and toast) then the maximum urine volume would be 2 liters.
Does this make sense?
The medullary interstitial is irrelevant because, in the absence of ADH, the tubules are locked and the tubular fluid is never exposed to that osmotic temptation.
last question
I have a question regarding the cause for the release of ADH in Hypervolemic Hyponatremia. I understand how in Hypovolemic Hyponatremia there is a release of ADH to allow for water reabsorption which helps to improve the decrease in volume (please correct me if that is incorrect),
Nailed it
but I do not understand why in Hypervolemic Hyponatremia there is release of ADH.
So I mention in the lecture that ADH has two masters, one is osmolality, increased serum osmolality stimulates ADH. This is operational in true hyponatremia since these patients have decreased osmolality. The other master is perfusion. In hypervolemia, think about heart failure, there is decreased perfusion of the baroreceptors of the kidney and aortic arch. This triggers a release of ADH. When ADH binds to V1 receptors in the vasculature it causes vasoconstriction (hence the other name for ADH, vasopressin), increasing blood pressure and improving perfusion (or at least this is what it hopes to do). When ADH hits the V2 receptors in the medullary collecting (and cortical) collecting duct it will trigger an increase in water reabsorption (through the insertion of aquaporin channels into the apical membrane, making the collecting tubule permeable to water).
Is this not exacerbating the excess volume, as increased ADH would cause increased water reabsorption and thus increase volume?
Yes, this may in fact be a maladaptive response. However a trial called EVEREST looked at pharmacologically blocking ADH with a drug called tolvaptan and it did not improve heart failure outcomes 😩
Further, is both result in decreased urine output and decreased urine sodium, how are the two differentiated? Are they differentiated simply by their causes?
YES!