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.

Published literature

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.

Hot Dog Therapy

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:

1. Survival
2. Cumulative time at home

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.

Hypokalemia and the 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:

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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.

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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

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.

Tea and toast syndrome

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!

A randomized clinical trial assessing the effect of automated medication-targeted alerts on acute kidney injury outcomes. F Perry Wilson, et al. Nature Communications 2023.

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Diagnostic Performance of Fractional Excretion of Sodium for the Differential Diagnosis of Acute Kidney Injury. Abdelhafez, Mohammad Et al. CJASN 2022.

And the editorial by Seethapathy H, and Fenves AZ CJASN 2022

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Weekend Hospital Admission, Acute Kidney Injury, and Mortality James et al JASN 2010

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KDIGO Clinical Practice Guideline for Acute Kidney Injury Kidney International 2012

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Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis Barbar S, NEJM 2018

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Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury STARRT-AKI Investigators NEJM 2020

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Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury The VA/NIH Acute Renal Failure Trial Network NEJM 2008

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Early versus standard initiation of renal replacement therapy in furosemide stress test non-responsive acute kidney injury patients (the FST trial) Nuttha Lumlertgul et al. Critical Care 2018

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Sodium bicarbonate therapy for patients with severe
metabolic acidaemia in the intensive care unit (BICAR-ICU):
a multicentre, open-label, randomised controlled, phase 3 trial. Samir Jaber The Lancet 2018.

Sometimes you listen to a podcast and wonder if the producers listen to their own podcast?

This week JASN dropped a podcast, Absolute CKD Progression Risk, that was poorly produced. This is a shame since the content was great. The host, Manjula Tamura, did a wonderful job interviewing Maria Clarissa Tio and Tariq Shafi on their fascinating study about the utility of absolute versus relative CKD risk. I loved the content. But the producers botched one of the steps in editing. Towards the end of editing, the producer needs to compress and normalize each track so that each speaker has roughly the same volume, and that volume is fairly loud. In this instance, Tamura was quiet, Tio was really quiet, and as I cranked up the volume to hear them, Shafi would blow out my eardrums. I spent the whole podcasts repeatedly turning volume up and down. Here is what it looks like:

I normalized the audio. It is not great, because I do not have the edited tracks in lossless audio, but I was able to improve the audio using Auphonic so that it looks like this:

Look at how the average volume is brought up quite a bit so that the difference between the quiet parts and loud parts is minimized. You can hear the result here:

And since I’m already here, might as well go all the way.

Why no show notes? Is a link to the manuscript too much to ask?

Today I was honored to give Medicine Grand Rounds at MedStar Health in Baltimore. Here is a wlk through and bibliography for this talk.

Title slide. Slides are available for download at:

Keynote What’s New in Nephron Town (31.7 MB)

PowerPoint What’s New in Nephron Town (16.9 MB) Note: I create, rehearse and deliver the presentation in Keynote. The PowerPoint version is a simple export of the Keynote presentation and often looks like garbage. If you want to see the presentation as it was meant to be, use Keynote. 

PDF What’s New in Nephron Town (9.8 MB) Note: The PDF shows only the final build of the slides and often that is not very illustrative of the point that the slide was trying to make. If you want to see the presentation as it was meant to be, use Keynote.

Outline of the talk. I originally outlined a section on aldosterone synthase inhibitors and IgA nephropathy, but ran out of time preparing for the lectures (aldosterone synthase) and thought it was not a great topic for general medicine audience (IgA nephroathy).

CDC data: SGLT2i use among Patients with CKD and Diabetes

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD AJKD

NO STONE Study: Dhayat, N. A. NEJM, 388(9), 781–791. (PubMed)

Craig Brater’s review of diuretics in the NEJM from 1998 (NEJM)

ALLHAT Hypertension results in JAMA. (PubMed)

CLICK Trial (PubMed)

The Diuretic Comparison Project. A pragmatic trial of HCTZ v chlorthalidone. (PubMed)

Meta-Analysis Comparing Torsemide Versus Furosemide in Patients With Heart Failure (PubMed)

TRANSFORM-HF Randomized Clinical Trial (PubMed)

AIN is a common finding on kidney biopsies done for AKI (at least at the University of Chicago, and among the elderly) (PubMed)

Urine eosinophils are not at diagnosing AIN. (PubMed)

Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis (PubMed)

Drug-Induced Acute Interstitial Nephritis. (CJASN)

Excellent review by the two guys who identified the gene. APOL1 Nephropathy from Genetics to Clinical Applications (CJASN)

Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants (PubMed)

Link to information about free genetic test for APOL1 at APOL1CKD.com

The CONVINCE Trial (NEJM)

Retrospective data on the speed of correction from Pennsylvania (PubMed)

Toronto data showing a lack of association between speed of correction and incidence of ODS (NEJM Evidence)

Boston data looking at risk of mortality by speed of correction in hyponatremia. (NEJM Evidence)

Multi-center data also showing increased mortality with slow correction of hyponatremia. (J of Crit Care)

This summer I was really optimistic. I was riding a #Flozin high that was being further buoyed by the successes of finerenone. Long dormant fields were yielding fresh life. How long has it been since we’ve had this much investigation into glomerulonephritis? So many trials. So many agents.

This is how I started a letter of rec I wrote this summer:

Can you feel it? Can you smell it? Yup, the winds of change have reached nephrology. Just as the most optimistic and sanguine nephrologists predicted, the new diagnostics, new therapies, and new hopes have blown in fresh enthusiasm for nephrology as a career. I am seeing more interns express interest in nephrology, more seniors asking for letters of recommendation, and more general interest for our specialty than I have seen in a score of years. Yes, the gains in the match results have been meager but change is coming and Dr. XXXXXX is a flag bearer for this renewed renal enthusiasm.

Well I was wrong. The winds of change were blowing us backward. After a good year for 2023’s starting class, this year’s match was a dud.

All those unfilled positions often make the training harder for the fellows that do match.
And residents see how hard the training is.
And they see the long and unpredictable hours.
And hospitalist looks better and better.

I love nephrology. I want nephrology to be a vibrant, attractive specialty, but what we are doing, isn’t working.

We have added training capacity like mad without building the demand for the positions. Look at the number of people matching every year (yellow). It is pretty flat since 2014. But the number of positions, and unfilled positions has grown steadily (blue).

This graph from Brian Carmody is interesting. Look where rheumatology and endocrinology are. Two specialties that are not lucrative. But they fill. Reliably and competitively. Lifestyle is important. This has been neglected in nephrology. We work hard, long, hours for sick patients. This should be an area we work on to remodel the specialty around new visions of work. Do we need to train nephro-hospitalists? Consider a one year fellowship with a focus on ICU and inpatient nephrology. Less clinic. Less GN. Less chronic dialysis. And this could be paired with an outpatient nephrology fellowship. Also one year. Modeled after endo or rheumatology with a clinic based schedule. Time dedicated to learning the skills and procedures to create and maintain dialysis access. If we removed the burden of inpatient rounding, fellows could master outpatient nephro and outpatient dialysis in a single year.

Splitting the roles would make the job easier and less chaotic.

Now look at ID the other end of the graph. ID and nephrology. Two specialties that can’t draw fellows. We need to fix this. This is an existential moment for the field.

Updates from Twitter

Poyan Mehr

I tend to agree with Joel. [this is the most important part] The discussion around compensation is valid but doesn’t explain the strong demand for lower-paying specialties. Besides, as an entrepreneurial nephrologist in private practice a 500-600k salary is not unusual. Money is not everything. Nephrology in the way we currently practice it is not attractive. And trainees see that. Let me explain:

Nephrologists remain proud generalists in an era of ever more complex diagnostic and treatment options. Other than dialysis, for the most part, we don’t own anything that our patients need. We need to beg other specialties to help us with fistula, catheter, biopsy, imaging, infusions, pheresis, and invasive volume assessment. Had we shown some pride, ownership, and support for clinical research as cardiology did, we would have now branched into several subspecialties and be more attractive, given the diverse opportunities catering to different preferences. Still, we also would have likely been more inventive in driving progress. Again, using cardiology as an example, cardiac imaging has advanced because cardiologists understand the clinical problems and have content expertise in finding technical solutions. Cardiac MR or CT wouldn’t be where it was if it were for the radiologists who are busy with 60 different body parts and would remain unaware of questions that would have never been asked.

But rather than creating a subspecialty track, nephrology dwells in the nostalgia of being a generalist. In 2023 still talking about the same electrolyte and acid base problems from 60 years ago with formulas validated in 10 med students.

We are risking to become a profession of mediocre generalists. The average rheumatologist is better at treating lupus nephritis than the average nephrologist. Not because they are the better doctors but because the nephrologist also has to master peritoneal dialysis, CRRT in ICU, post-transplant renal care, hypoNa with seizure, and on and on. How do we expect trainees observing us (jacks of all trades and master of none) and getting inspired??

Nephrology as a specialty needs to have either a radical makeover or will diminish and perish, with endo taking over electrolyte management, rheum autoimmune disorders, cardiology volume and BP, critical care CRRT, and so on. Some say that would be good so. Because it would be better for the patients.

And though this was not in response to this essay it is a good thought

I, too, think about the #nephrology match, not that I can do much about it.

Crazy question: What changed in 2011, that might have precipitated a trend that would fully manifest a few years later?

Crazy answer: ESRD PPS. pic.twitter.com/LXsH8fVMdw

— Eric Weinhandl (@eric_weinhandl) November 30, 2023