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:
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 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
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
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?
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.
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
Weekend Hospital Admission, Acute Kidney Injury, and Mortality James et al JASN 2010
Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis Barbar S, NEJM 2018
Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury STARRT-AKI Investigators NEJM 2020
Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury The VA/NIH Acute Renal Failure Trial Network NEJM 2008
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
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:
For the last half year or so, I have been writing a newsletter for MashUpMD. I grab some interesting lingos from around the web, string them together with some of my thoughts and they send it out packaged with a handful of ads. And I get paid.
All and all it feels like blogging. Having someone give me a deadline and a small check apparently is what it took to bring me back to blogging.
I am going to try to bring these posts to PBFluids, but what you should really do is subscribe to me through MashUpMD.
Here is the most recent newsletter…
Hello and welcome to the NKF Spring Clinical Meetings. Follow @Neph_Times on X for updates. I will be live-tweeting the meeting on that account. Also, come to the Westin hotel bar tonight (Wednesday) to say “hi” and clink glasses with the “NephJC” posse.
Today’s email does a deep dive into an unfortunate case of osmotic demyelinating syndrome. We should try to learn all we can from these bad outcomes to protect future patients.
The next group of links concerns a new study in JAMA that aims to improve our basic cardiovascular (CV) risk models by adding contemporary CV blood tests. It does not go well and is a cautionary tale for all of those business plans built around high-margin executive physicals.
I close out with the latest results of the USMLE part 1. This is the second set of scores since the test went pass-fail in 2022, and the pass rate is down… again. But don’t jump to any conclusions before reading the thread in the link.
Thanks, and see you at the NKF Spring Clinical Meetings.
Terrible case of a patient who was admitted with hyponatremia, sodium 118 mmol/L. Using 3% saline, the team brought the sodium up to 125 but it then drifted back down to 121. This prompted a nephrology consult who recommended salt tablets, fluid restriction and tolvaptan 15mg. The next day the sodium was up to 125 and the then nephrologist bumped the tolvaptan to 30 mg. The next day the sodium riose 133 and the patient was discharged on 30 mg of tolvaptan daily. The following day the patient was confused and had sodium is 152! The patient presented to the ER the next day with a sodium of 170! I don’t use tolvaptan often, but when I do, I don’t pair it with another therapy for hyponatremia (no fluid restriction, no salt tablets, no urea).
This article by Rastogi and Velez looked at both tolvaptan’s efficacy and the risk of sodium over correction at two different doses. They found that the standard 15 mg dose regularly over corrects the sodium, using 8 mEq/L per day as their target, in SIADH. This is important. This study was practice changing for me. When the patient has SIADH, and I want to use tolvaptan, I use 7.5 mg. If there was a lower dose I would use that, but since tolvaptan is a triangular, crumbly pill, it is had to get a reliable dose less than 7.5 mg.
Tolvaptan’s effectiveness is highly dependent on the diagnosis. The risk of rapid correction with 15 mg was 84% less likely with heart failure as compared to SIADH. The authors found a low BUN (consistent with SIADH) and a low sodium to be the best predictors of rapid correction. The low sodium is consistently a risk factor for rapid correction. As sodium’s fall below 120 be more and more careful about overcorrection. I don’t use tolvaptan in those patients, and prefer 3% saline because I can turn it off if things go sideways.
These investigators looked at over 160,000 people from 28 cohorts in 12 countries to try to improve the traditional CV risk assessment. Surely adding high sensitivity troponin-I, nt-ProBNP, and hsCRP to the traditional risk factors (age, gender, race, systolic blood pressure, HDL and total cholesterol, smoking, and diabetes status) would provide greater accuracy, and they do! But the headline is how little they move the needle. The area under the curve (or C-statistic) moved from 0.812 with traditional risk factors to 0.8194 with the addition of all 4 blood tests!
Bryan Carmody does his usual amazing job at dissecting this data without the typical sky-is-falling mentality found on X. Do not miss the expanded Y graph and the reminder of what the test scores means for individual test takers and their reproducibility.
Follow MashupMD @MdMashup to stay up to date on the latest topics your peers are discussing.
PowerPointWhat’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.
PDFWhat’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).
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.
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?
Part of the inspiration for this came from an epic message on the Channel Your Enthusiasm back channel by Roger Rodby
Here is the draft of the script.
Diffusive vs Convective clearance
I was teaching the third year medical students about acute kidney injury and the lecture begins with a brief history of extracorporeal dialysis for AKI. And I asked a student what extracorporeal dialysis was, and he correctly identified it as “dialysis outside the body.”
Since the ironclad law of the Socratic Method is that every correct answer is rewarded with another, harder, question, I replied, “Can you think of any example of intracorporeal dialysis?” The right answer is peritoneal dialysis, but he said , “The kidney?”
And off on a tangent we went… Does the kidney even do dialysis? No. The kidney does not use diffusion to clean the blood. Clearance is provided by convection at the glomerulus. Plasma is squeezed through the slit diaphragms of the podocytes in the glomerulus but besides the lack of protein, the solute composition on both sides of that membrane is essentially identical.
The kidney does not clear the blood by diffusion, the defining characteristic of dialysis, but rather by convection. How does that work? Glad you asked. Take Creatinine. The creatinine on both sides of the podocyte is the same, 4.4 mg/dL in this example.
4.4 mg per dL x a GFR of 25 mL per minute x 1440 minutes in a day divided my 100 mL in a dL comes to 1584 mg of creatinine filtered.
That is just about the amount of creatinine produced by a typical person a day.
So convective clearance can clear all of the creatinine produced everyday, the additional creatinine secreted in the proximal tubule is just gravy.
What about sodium?
138 mEq/L x a GFR of 25 mL per minute x 1440 minutes in a day divided by 1000 mL in a L comes to 4968 mE of creatinine filtered.
This is a problem since we only consume around 100-200 mEq of sodium a day. So this where the tubules earn their stripes by reabsorbing all the excess filtered sodium to keep us from peeing ourselves to death.
So these two examples demonstrate an important principle of convective clearance, it is better for clearing things at a high concentration than at a low concentration. In fact, a GFR of 1 is enough to clear a typical sodium daily load.
138 x 1 ml/min x 1440 min/day divided by 1000 ml/L = 198 mEq/day
This why even a tiny residual renal function makes a huge difference in dialysis patients.
But that same GFR of 1 would only clear
4.4 x 1 ml/min x 1440 divided by 100 ml/dL = 63 mg of creatinine only about 4% of the daily creatinine load.*
*This calculation is highly dependant on the serum Cr concentration, which would be a lot higher than 4.4 if the GFR was 1, but since a GFR of 1 in incompatible with life, the patient would also be getting renal replacement therapy, so it is hard to know where the serum Cr would actually be.
So after explaining that the kidney didn’t actually do dialysis, or anything remotely close to dialysis. I asked if there was an organ that did do dialysis? Or, more specifrically, used diffusion for clearance. Answers from the crowd:
Liver > nope
Spleen > nope
Skin > nope
And finally, Lung? Yup.
The lung clears carbon dioxide from the body and absorbs oxygen by setting up a setting where the gasses move down their respective concentration gradients across a semipermeable membrane. You know, like dialysis.
A ventilator is not really like an artificial lung, in the way a dialysis machine replaces the core function of a kidney. It provides flow, but no clearance. We still are dependent on the alveolar membrane for oxygen absorption and carbon dioxide clearance.
But ECMO is an artificial lung and fully replaces the alveoli and uses the principles of dialysis to clear carbon dioxide and move oxygen into the blood. So at some level, ECMO is closer to the lung than dialysis is to the kidney.
One final note on this thread is in regards to dialysis and convection. The kidneys work by convective clearance but our primary means of replacing them is by diffusive clearance. However this summer we saw a randomized controlled trial of modifying dialysis to use convection rather than diffusion…and the result? Significant reduction in total mortality.
We don’t get a lot of wins in dialysis, so when we get one, we pay attention.
The script isn’t exact because I have to do some edits to meet the character limits of tweets.
Here are the Keynote slides that I used to create the gifs.
I have a long-time patient who came in yesterday and we were reviewing their labs together and noted a tremendous success. The patient’s albuminuria has fallen 90% since 2018. This is due to adding and then maximizing losartan, adding dapagliflozin, and most recently starting finerenone.
Here is the albuminuria over time:
Over that time their eGFR looks like this:
How should we square the recent drop in eGFR with the reduction proteinuria? We typically switch to a risk based model, here are their Tangri KFRE scores over time:
I was quite surprised to see the KFRE rise over time despite the 90% reduction in albuminuria. I am not changing therapy. The eGFR is nearly intact and I am not going to tiny changes in creatinine (the most recent jump was less than 0.2 mg/dL) guide therapy decisions. I am going to continue to ride these medications which have repeatedly been shown to protect kidneys (and hearts).
