The latest salvo in the hyponatremia wars takes off where Seethapathy left us (NEJM Evidence | NephJC). Last week, Juan Carlos Ayus published his latest study (JAMA Internal Medicine) on hyponatremia, a meta analysis of patient outcomes in the management of hyponatremia.

If you are not aware of Ayus’ prior hits, you should take a look.

Retrospective data that looks at speed of correction and uses that to look at outcomes has been a staple in hyponatremia research for decades. It is the basis for the current, decades-old, hyponatremia guidelines from the US and Europe. However, until recently the only outcome of interest was osmotic demyelinating syndrome (ODS, and boy is that a loaded term that probably should be re-litigated, see Seethapathy’s grand rounds in Ottawa, YouTube). When looking at ODS, a pattern emerges that slower correction is associated with fewer cases of hyponatremia, however it is unusual to look at a case series and only care about one outcome. If we pull back a bit and look at all the outcomes that matter, things like length of stay and mortality, the situation changes. In Ayus’ meta-analysis, the primary outcome was mortality and just like in Seethapathy, slower correction was associated with increased mortality. Not a great look. And I think the orders of magnitude are important here.

Patients that experience faster correction of sodium consistently have better clinical outcomes in these sorts of analysis. And the rate of ODS is vanishingly low, expecially with the looming specter of death. The focus on ODS makes us ignore what an ominous sign hyponatremia really is. I can’t think of an electrolyte with such a frightening association with mortality.

The obvious weakness with this type of analysis is they do not provide any insight as to why the correction was slow. While we like to think that the slow correctors are populated by patients with bespeckled nephrologists carefully calculating sodium and water prescriptions according to the Edelman formula, but the reality is that the patients with slow correction is populated by people with liver and heart disease that are not easy to fix. And their prolonged length of stay and poor outcomes are driven by these dismal diagnosis.

And what of the rapid correctors? This cohort gets better quickly, not because cowboy nephrologists are slinging 3% saline to rapidly bring the sodium to heal, no, rather these are patients whose body wants a normal sodium and as soon as it is able to reject the excess water it will return the sodium to normal. And this is often despite the best intention of the treatment team. In Sterns’ study on the DDAVP clamp, 25% of patients in the control group (historic controls for their retrospective case series) made more than 1200 ml of urine an hour.

The slow correctors is populated by patients who are so ill that their bodies have rejected sodium and water homeostasis in the name of perfusion. Not a good place to be, hence the bad outcomes. While the fast correctors is populated by people whose physiology remains committed to sodium and water homeostasis. It is not hard to see why disease so severe that it rewrites the laws of homeostasis would have increased rates of devastating outcomes.

More simply the results are confounded.

Does the confounding explain all of the excess mortality?

Is it that far fetched to believe that the low sodium itself could contribute at least a little to the excess mortality seen with hyponatremia? It seems likely that something the body spends so much energy trying to keep regulated would be important and have an effect on outcomes. And given the rarity of CPM/ODS, even a small residual effect would swamp the concern for CPM/ODS because not only is ODS, rarer than we were lead to believe, the outcomes of ODS are not as bad as we were taught.

In Jason George’s study of nearly 1,500 people with sodiums less than 120, they had 9 patients with ODS on imaging. In terms of neurologic outcomes among these 9, “five patients with documented osmotic demyelination had recovery with no neurologic deficits, two patients died from unrelated causes, and two were lost to follow-up.”

When you look at Ayus’ meta-analysis of hyponatremia are you sure there is no residual signal? Because the people promoting ever slower rates of correction to avoid CPM feel that there is nothing on the other side of the balance pan. That slowing the rates of correction will always be justified. That it is okay to prolong hospitalization by any length of time. That we should adopt interventions like DDAVP clamps without any prospective data because the risk of ODS is so important that concern for this complication should drive the therapeutics in hyponatremia.

And while we are adopting DDAVP, we should restrict and avoid tolvaptan, not because it causes ODS, there were no cases in Schrier’s Phase three SALT1 and SALT2 trials, but because it may correct the sodium faster than guidelines suggest. Now we are not even worried about ODS, but rather the purported risk factor for ODS, speed of correction.

We adopted the risk factor rather than the outcome in the case of hypertension. We want to avoid the stroke and CV death, so we treat the blood pressure to a target BP. But the hypertension guys didn’t just look at retrospective data. They went out and did the work to see if treating blood pressure avoided the outcome, and it did. We should demand similar certainty for the treatment of hyponatremia.

We no longer should accept retrospective observational data. The Hyponatremia Intervention Trial (HIT, Protocol and rational for design publication in PubMed) showed that we could do prospective, randomized trials, in the treatment of hyponatremia. The study was not positive, but it was important. Here are my tweets from the Late Breaking and High Impact Clinical Trial Session at Kidney Week where the results were announced. We are still awaiting publication.

Made it to the LBCT sessionAnd it is a hyponatremia trial!#KidneyWk

— Joel Topf (@kidneyboy.bsky.social) 2024-10-26T17:47:32Z

It is time to demand this. Hyponatremia is too common and for us to trust that the mortality signal is entirely a statistical mirage.

Monday night I had my biggest “hit” on Bluesky. I had been tipped about a forthcoming hyponatremia meta-analysis in JAMA Internal Medicine at Kidney Week and so I was primed when it was posted to the JAMA website Monday evening. As soon as I saw it I posted to Bluesky:

Honey, stop what you're doing, new hyponatremia research just dropped!What's it say?It looks like slow correction is associated with worse outcomes, like death and length of stay!Was it just a small study?No, it was a meta-analysis of almost 12,000 patients!jamanetwork.com/journals/jam…

— Joel Topf (@kidneyboy.bsky.social) 2024-11-19T04:51:11.204Z

(OMG, it is so cool to be able to embed a tweet in a blog post again!

So at the time of this blog post it has 290 likes, 105 retweets, and 41 replies.

The next morning, I saw that my post was gaining steam, so I copy-pasted to Twitter at 9:30 AM. Later that day Swap saw that I posted in both places and declared Bluesky the winner.

So @kidneyboy.bsky.social has 15 times more followers on Xitter (along with algorithm boosting blue check) versus a ‘BlueSky Elder’ coveted label here Same post comparison below It’s a #BlueSky blowout #NephSky

— Swapnil Hiremath (@hswapnil.bsky.social) 2024-11-19T19:29:08.277Z

But the Bluesky post had a nine hour head start . How does the twitter post look now compared to Bluesky?

The Twitter post has 27 replies compared to 41 on Bluesky. I find replies to be the best form of engagement, Retweets are similar at 105 on Bluesky versus 129 on Twitter, but Twitter’s 603 hearts and 388 bookmarks swamps Bluesky’s 209 hearts.

But it really doesn’t matter. I’m all in on Bluesky. I like the philosophy. I like the aesthetic. And it is where my people are.

When I first started this blog, it automatically sent a tweet when I had a new post. This continued until Musk disabled a number of APIs, including the one that allowed automatic posting.

Now I am disentangling myself from Twitter and embedding myself in Bluesky. Hopefully, this will post there automatically.

Fingers crossed.

Testing 1…2…3…Testing

I am still in the “amazed by what AI can do” stage

Here is me prompt

i am teaching a class on electrolyte abnormalities for nephrologists. What would be good tricky things to teach

I then ran my prompt through an AI to make my prompt “better” This AI is called PromptPerfect. Here is what it came up with:

As part of my curriculum for a class aimed at nephrologists focusing on electrolyte abnormalities, I am seeking innovative and challenging concepts that can enhance the learning experience. The goal is to identify complex scenarios or case studies that delve into the nuances of electrolyte homeostasis, including mechanisms, clinical implications, and diagnostic challenges. I would appreciate suggestions for specific topics that could provoke critical thinking and discussion among the attendees, such as rare electrolyte disorders, atypical presentations, or the interplay between various electrolytes in different clinical contexts. Additionally, please provide a structured outline of how these concepts can be presented, including key points, potential teaching methods, and examples that could facilitate understanding.

And here is the output that Chat GPT4o came up with:

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Curriculum Outline: Innovative and Challenging Electrolyte Abnormalities for Nephrologists

Module 1: Rare Electrolyte Disorders – Uncommon Mechanisms and Diagnosis

Key Concept: Understanding rare electrolyte disturbances that involve complex mechanisms and atypical presentations.

Key Topics to Discuss:

1. Hyperkalemic Periodic Paralysis (HPP)
   • Mechanism: Mutations in the sodium channel (SCN4A), leading to abnormal potassium shifts during exercise or fasting.
   • Clinical Implication: Presentation with episodic muscle weakness and hyperkalemia.
   • Diagnostic Challenge: Distinguishing HPP from other causes of hyperkalemia, such as renal failure or medications.
   • Teaching Method:
     • Interactive Case Discussion: Present a case of a young athlete with recurrent episodes of weakness and hyperkalemia. Explore diagnostic tests (genetic testing, muscle biopsy).
     • Group Activity: Have the class brainstorm possible causes of episodic hyperkalemia and narrow down to rare causes like HPP.
2. Familial Hyperkalemic Hypertension (FHHt)
   • Mechanism: Mutations in the WNK1 and WNK4 genes leading to excessive sodium retention and secondary hyperkalemia.
   • Clinical Implication: Hypertension with normal or elevated potassium despite low renin and aldosterone.
   • Diagnostic Challenge: Differentiating FHHt from primary hyperaldosteronism or renovascular hypertension.
   • Teaching Method:
     • Case Study: Present a hypertensive patient with hyperkalemia, and have learners differentiate between FHHt and other causes of secondary hypertension.
     • Interactive Q&A: Ask the learners to discuss how genetic testing can be used for diagnosis, and compare the pathophysiology with other causes of secondary hypertension.
3. Tumor Lysis Syndrome (TLS) and Electrolyte Imbalances
   • Mechanism: Rapid release of intracellular electrolytes (potassium, phosphate, and uric acid) due to tumor cell lysis.
   • Clinical Implication: TLS can cause hyperkalemia, hyperphosphatemia, and hypocalcemia, along with acute kidney injury (AKI).
   • Diagnostic Challenge: Early detection of TLS in the absence of clinical symptoms; managing high-risk patients pre-emptively.
   • Teaching Method:
     • Case Study: Present a cancer patient undergoing chemotherapy with electrolyte abnormalities and acute kidney injury. Discuss management strategies, including allopurinol, rasburicase, and hydration.
     • Interactive Poll: Ask learners how they would manage a patient at risk of TLS in the first 48 hours.

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Module 2: Electrolyte Imbalance in Multi-System Disease

Key Concept: The interplay between various electrolytes in patients with complex co-morbidities and multi-system disease.

Key Topics to Discuss:

1. Hyponatremia in Heart Failure and Cirrhosis
   • Mechanism: Discuss hypervolemic hyponatremia in the context of heart failure (low cardiac output, increased ADH release) and cirrhosis (portal hypertension, ascites, altered renal perfusion).
   • Clinical Implication: Both conditions may result in SIADH-like patterns with hypovolemic and euvolemic hyponatremia.
   • Diagnostic Challenge: Distinguishing between cirrhosis with ascites and heart failure with ascites as causes of hyponatremia.
   • Teaching Method:
     • Case Comparison: Present two cases of hyponatremia—one in a patient with heart failure and the other with cirrhosis—and have learners compare and contrast their approaches to diagnosis and management.
     • Group Discussion: Have attendees discuss the pathophysiology of hepatorenal syndromeand cardiorenal syndrome as part of electrolyte disturbances.
2. Potassium Abnormalities in Diabetic Ketoacidosis (DKA)
   • Mechanism: Insulin deficiency, acidosis, and shifts in potassium from the intracellular to extracellular space in DKA.
   • Clinical Implication: Potassium levels can be falsely elevated on presentation due to transcellular shifts, and may drop quickly with insulin therapy.
   • Diagnostic Challenge: Assessing potassium levels and deciding when and how to replete potassium during DKA treatment.
   • Teaching Method:
     • Interactive Case Discussion: Present a case of a diabetic patient with hyperkalemia and acidosis. Discuss the initial approach to potassium monitoring and replacement during DKA management.
     • Problem-Solving Exercise: Have learners calculate the correct amount of potassium to replete in DKA while managing acid-base status and avoiding hypokalemia.

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Module 3: Complex Electrolyte Interactions and Their Clinical Impact

Key Concept: Understanding the dynamic interplay between multiple electrolytes in clinical scenarios, and how changes in one can impact others.

Key Topics to Discuss:

1. The Calcium-Phosphate Paradox in Chronic Kidney Disease
   • Mechanism: In CKD, impaired phosphate excretion leads to elevated phosphate levels, which bind to calcium and precipitate in tissues, contributing to vascular calcification and secondary hyperparathyroidism.
   • Clinical Implication: Elevated calcium-phosphate product is a risk factor for cardiovascular morbidity.
   • Diagnostic Challenge: Monitoring and managing the calcium-phosphate product in the context of dialysis or advanced CKD.
   • Teaching Method:
     • Interactive Discussion: Present a dialysis patient with elevated calcium, phosphate, and secondary hyperparathyroidism. Have learners propose management strategies to reduce the calcium-phosphate product.
     • Case Study: Explore the role of calcimimetics, phosphate binders, and vitamin D analogs in controlling the calcium-phosphate product.
2. Magnesium and Potassium Imbalances: The Subtle Interplay
   • Mechanism: Hypomagnesemia often accompanies hypokalemia, and correcting hypokalemia without addressing magnesium deficiency can lead to refractory hypokalemia.
   • Clinical Implication: Magnesium plays a crucial role in potassium regulation, and untreated magnesium deficiency can hinder recovery of normal potassium levels.
   • Diagnostic Challenge: Identifying hypomagnesemia in patients with unexplained hypokalemia.
   • Teaching Method:
     • Case Presentation: Present a patient with refractory hypokalemia that doesn’t improve despite treatment. Lead a discussion on the potential underlying magnesium deficiency and the rationale for magnesium repletion.
     • Interactive Exercise: Have learners analyze lab results and decide whether magnesium levels should be checked in cases of hypokalemia.
3. Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors and Electrolyte Shifts
   • Mechanism: SGLT2 inhibitors, used in diabetes and CKD, can cause increased sodium excretion, leading to fluid shifts and electrolyte disturbances (e.g., hyponatremia, hypokalemia).
   • Clinical Implication: The risk of electrolyte abnormalities is increased with dehydration,diuretics, or acute kidney injury in patients on SGLT2 inhibitors.
   • Diagnostic Challenge: Early identification of electrolyte imbalances when patients are on SGLT2 inhibitors, especially during periods of acute illness or volume depletion.
   • Teaching Method:
     • Case Study: Present a patient on SGLT2 inhibitors who presents with confusion and low sodium. Discuss the role of SGLT2 inhibitors in electrolyte homeostasis and how to adjust treatment when using these drugs.
     • Interactive Poll: Ask learners to suggest steps for managing a patient on SGLT2 inhibitors who presents with dehydration and electrolyte abnormalities.

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Teaching Methods and Approaches

1. Case-Based Learning: Provide complex, real-world cases where the students can apply their knowledge of electrolyte abnormalities in clinical scenarios. Case discussions should prompt learners to think critically about diagnosis, pathophysiology, and management.
2. Small Group Discussions: Break learners into smaller groups to tackle specific topics or case studies. Afterward, have each group present their findings and management approach to the class.
3. Interactive Polls and Quizzes: Use technology (e.g., Kahoot, Mentimeter) to ask clinical questions and prompt learners to choose the best answer. This can be used to initiate discussions and clarify concepts.
4. Role-Playing and Simulations: Use role-playing to simulate difficult clinical situations (e.g., managing a patient with complex electrolyte imbalances during a crisis). Simulations can help learners practice decision-making under pressure.
5. Expert Panel Discussions: Bring in experts to discuss the nuances of managing rare or complex electrolyte disorders, especially those with genetic or multi-system involvement.

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Conclusion

By focusing on rare disorders, complex interactions, and multi-system involvement, you can stimulate deep clinical reasoning and promote active learning. Encourage learners to approach electrolyte abnormalities not only as isolated issues but also as part of a broader clinical context, where underlying mechanisms, patient history, and comorbidities significantly influence diagnosis and management.

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There are some significant mistakes. Secondary hyperparathyroidism is associated with low a calcium, not a high calcium. And the SGLT2i section in Module 3 would have to be entirely abandoned. But for ten minutes of just fucking around with Chat GHPT it is pretty complete and looks like it would make for a pretty compelling curriculum.

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.

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I was a supplement hater for a long time. I was a supplement hater even after I begrudgingly realized how critical it was to truly understand a study.

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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:

1. When you arrive at the website you need to click calculate to get to the calculator. Then after entering the four-variables it requires another click to bypass entering information for the 8-variable version of the KFRE. I never want to so that, another wasted screen and button press.
2. It does not remember units. My albuminuria is always measured in mg/g. All of my patients are from North America. Why won’t this tool remember this?
3. Once you have a result there is no way to navigate back to the calculation page except to reload the home page kidneyfailurerisk.com. The URL for the result page is just kidneyfailurerisk.com, so the forward and back arrows are useless because as far as the browser is concerned you have not left the main page.

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.

The Tweet (actually in this case a Tweetorial)

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).