Super fun discussion on Twitter that has spilled out over the last few days. It began with this tweet about Nayan’s take on the latest MRI imaging during dialysis.
The original article is here and I’m a bit embarrassed about my sensationalization being a bit overwrought.
Forunaltely, it did trigger a great rolling conversation about the future of dialysis and by extension, nephrology. It may be difficult to recreate the discussion from that original tweet, so here are some key tweets:
I remain hopeful for the day when most of the job for ESKD is managing implantable artificial kidneys or xenotransplants / kidney on a scaffold grown in vats. We need to get to the point where most dialysis is relegated to the hospital.
I will make a bolder prediction : the HD business landscape will be dramatically different in the next 5 years: low margins, "harvesting" of the "pipeline" and patients by COVID and PASC, hopefully deployment of SGLT2i/MRAs/GLP1 at scale & a couple of fiscal crises lie ahead.
— ChristosArgyropoulos MD, PhD FlozinatorInChief (@ChristosArgyrop) March 13, 2023
This whole thread is like just about every dinner meeting lately. It starts with a cool study about the effects of the dialysis on the brain and ends with all our personal forecasts about CKD business.
This is another downstream "effect" of VBC. I am getting bored!!
But this prognostication is focused on emerging transplant technologies and fails to capture the full breadth of nephrology transformation that we are seeing. With the emergence of Flozins, GLP1 agonists, MRAs (both steroidal and non-steroidal) as well as the increased interest and development of novel treatment targets, it is not a leap to say that nephrology in 10 years will look very different than it is today.
How will we mark that development? My poll of when will more than half of transplants come from non-human sources is a specific and quantifiable time that will represent a sea change in transplant. A marker that represents a change not in potential but in delivery. So how will we mark that moment in nephrology at large? I would argue that it happens when we see consistent year over year fall in the number of prevalent dialysis patients (in-center and home) for four consecutive years.
So how long until the combination of slower CKD progression, increased transplantation, and, unfortunately part of the equation, continued stagnation in dialysis longevity, result in consistently falling dialysis prevalence?
You calculate the osmolarity based on the measured values because everything is equally diluted by the water shift from the hyperglycemia.
— Screaming Pectoriloquy (๐๐ฉ๐๐๐ฆ๐ฅ๐๐) (@Caulimovirus) November 24, 2022
And a screenshot for when Twitter disappears.
A ten percent reduction in sodium drops it from stone cold normal to rather significant hyponatremia. This is a great example of how precisely sodium is regulated. Sodium regulation is tighter than all other ions. Look at a CMP with calcium, phosphorus, and magnesium added in. (Data is from UCSF).
BUN (233%) and creatinine (117%) are not regulated anywhere close to how electrolytes are regulated. Get those guys out of here.
And, the sodium (7%) and chloride (10%) range are nearly identical. Outside of the anion gap, I almost always ignore chloride.
So let’s simplify this and remove the outliers and shadow.
Look at how tightly sodium is regulated. Regulation of second place, calcium, is THREE times as relaxed.
Every electrolyte is important, but regulating sodium regulates the tonicity in all 42 liters of the internal ocean. Apparently, this is important and sodium is allowed to wander only slightly.
The destruction of Twitter seems to continue. Tweet threads like this do not make me optimistic about the future, so download your Twitter experience before Twitter.com is nothing more than a empty website.
[1/4] One of the fascinating things is watching Twitterโs behavior change, hour after hour, as various microservices go offline. Itโs a real testament to that approach that things mostly work as various features wink out of existence.
After requesting your archive you need to wait for twitter to package up your experience. When they do you will see this on your time line
And this in your email
After I requested my Twitter Archive, it took two days for mine to be available. This is longer than I have seen in the past, makes me think there is a mad rush for the door and a lot of people are doing this.
When you click on the tweet it asks you for your password and then lets you download your Twitter Archive.
It can be a big file. Mine is 5.1 gigs. The archive it is a folder containing two other folders and a text file called Your Archive.html. Launch that and you will be greeted with this.
Clicking on “Tweets” allows you to see your entire history with a nice search function on the right.
I don’t know where Twitter is headed but it doesn’t seem good and I think in the next month or two (weeks?) there is a real possibility of going to twitter.com and seeing a blank page.
#NephTwitter has developed into a wonderful community and if Twitter disappears the community will be forced into a diaspora. NephJC has the podcasts, the newsletter, and the website to communicate our next moves. If you do not subscribe to the newsletter, now would be a good time to do so.
This coming Tuesday, November 15th, NephJC will be discussing EMPA-Kidney and after that discussion ends at 10pm we will be hosting a Twitter Spaces audio chat to discuss about what to do “After Twitter.”
In the mean time, if you have been investing in Twitter for a year, five years, ten years, fourteen years, then you should download your Twitter archive.
To do this go to your profile page and press “More” It will look like this. Then click on “Settings and Support”
From “Settings and Support” Click on Your Account and then Download an archive of your posts.
Twitter will ask you for your password and then it will e-mail you a note when the archive ready to download.
I spoke before thinking. I spoke loudly. I spoke and I hurt people. People who mean a lot to me. I hurt a mission that means everything to me.
I tweeted in anger and I said things to an imaginary place inside my phone that I would never say in person.
I spoke without grace. I spoke with a foul mouth.
We say it all the time, โDonโt Tweet Angry,โ and itโs because we know the internet has a way of making us forget there are humans on the other end of the tube. In this case, the humans were people I know. People who are passionate, conscientious, dedicated, and good.
This is bad. This is not who I aspire to be. I am sorry.
I hurt people that are contributing to this great collective, this great educational mission. #NephTwitter is the greatest FOAMed effort in Medicine. #NephTwitter is what every specialty in medicine should aspire to. And the Nephrologists running The GlomCon Fellowship are doing a great job building #NephTwitter. I should never do anything to tear this down. I am profoundly sorry.
Letโs keep AngryTwitter as far from #NephTwitter as possible.
A number of years ago, I was invited to write a chapter introducing sodium and water for a new medical text book under the Scientific American brand. I remember being disappointed that I didn’t get hypo- or hypernatremia and being stymied for awhile before I figured out how I wanted to the topic. Ultimately, I had a great time writing the chapter and, at least at the time. I was quite proud of the work. The textbook was somehow abandoned somewhere between inviting the chapter authors and publication. The publisher pivoted to some online component that was supposed to rise out of the ashes of the text book and they asked me to do additional work. I never did that work and they never asked a second time, so I don’t know if that ever came to fruition.
Anyways, this chapter has been sitting in the bowels of my Google Drive for years.
I hadn’t thought about this until recording chapter seven of Channel Your Enthusiasm podcast where we are reading through Burton Rose’s classic Clinical Physiology of Acid Base and Electrolyte Disorders. In Chapter 7, Rose discussed using simple math to predict the changes in intracellular and extracellular fluid volume following various fluid and solute challenges. This is exactly what I did in my Scientific American chapter. I found the exercise to be a profound moment of understanding.
As I was spelunking in the depths of my hard drive I came across this document from the end of 2013. We had completed the inaugural year of NephMadness and after returning home from Kidney Week, Matt, Edgar, Kenar and myself put together a proposal to make NephMadness a recurring event.
It is remarkable that we were putting the pitch together in November and December when the contest would launch in March. Now NephMadness is a 9 month month process with planning usually beginning in June.
Some notes from the document. In 2014, we were still trying to figure out how to determine the winners. I love this paragraph, especially, “One down side of this is that it will make the contest appear rigged, which it actually is.”
I also like this part which gives you an idea of how small not only NephMadness was in 2013, but how small the footprint for online nephrology education was:
1. We were highlighted at the AJKD editorial board meeting to a geographically diverse, packed room. Dr. Levey asked how many people participated in the first NephMadness and almost no one raised their hand.
2. A day later we demonstrated NephMadness to a room of cutting-edge educators. I got the feeling, besides the usual suspects (Edgar Lerma, Pascale Lane, Tejas Desai, etc.) no one in the room had heard of the campaign. The crazy bit was, I donโt think many had heard of PBFluids.com or NephronPower.com. This really reinforced to me how limited our exposure was. We had reached out to a lot of people and had dramatically boosted the traffic to the blog but to a large extent we were preaching to the choir.
And lastly, in the publicity section we were excited about getting featured on Dr. Mike SevillasPodcast, which has since gone defunct after 372 episodes!
So here it is for all your NephMadness nostalgia needs…
Iโm in the taxi leaving #NKFClinical (or at least I was when I started writing this) and if it wasnโt the first in-person meeting that most of us have been to since the onset of the pandemic, it would be remembered as “the one where Korsuva was launched.”
Room key and business cards from the Vifor Army at the meeting
During the meeting there was a buzz about this drug. And the buzz was around the two phase-3 trials, KALM-1 and KALM-2. The buzz is around the decreased effect size from KALM-1 to KALM-2. Difelikefalin met it’s primary endpoint to reduced severe itching in KALM-2, but the effect size is notably smaller than in KALM-1.
The results from KALM-1The results from KALM-2
The effect size could have been larger, the same, or smaller than KALM-1. Iโm not sure how much shade should be cast that it turned out to be smaller, especially as it remains better than placebo.
But my primary concern is that focusing on effect size misses the point.
We are used to prescribing invisible drugs; drugs that move a magical end point like cholesterol or blood pressure. Lowering cholesterol does not make patients feel better it just loads the dice so that when fate rolls them every year your patient is less likely to have an acute MI. Same with antihypertensives, SGLT2 inhibitors and almost everything we use except for pain killers. If the patient asks the doctor if the drug is working it is an invisible drug. If the doctor asks the patient if the drug is working it is a visible drug.
I was a sight PI on KALM-1, which means I am one of the few nephrologists who has real world experience with the drug. During KALM-1 I saw people have remarkable response to study drug and I saw people people have no response to study drug. Since I was blinded, I assumed that everyone having a good outcome was on drug and everyone without a response was on placebo. That is always a fairy tale and I now know that wasnโt true. Both KALM trials showed a big placebo effect (not as big as difelikefalen, but big). The placebo effect was large enough to convince me that all the success I have seen with diphenhydramine, gabapentin, steroid creams (none of which have robust supportive data), was likely just placebo effect. And now we are about to get the opportunity to switch everyone who has failed placebo to start an effective drug. But the wonderful thing is we do not have to just hope the drug is working, we can just ask our patients. Use it for a few months and ask people if they are better. No need to worry about the statistical effect size, all we need to do is assess the effect size in the patient in front of us. If the drug is not working stop the drug. However, be aware, a few weeks later the patient may tell you how much they liked it and that it was helping more than they recognized. My study patients were most vocal after the study concluded and everyone stopped study drug and went back to usual care. Multiple patients begged to enroll in extension studies, different investigations, anything to get access to difelikefalin…because uremic pruritus is miserable.
Difelikefalin is the first drug we have in nephrology whose specific purpose is to alleviate symptoms. This is a different type of drug and we need to retrain ourselves to shift our view on effect side.
After I wrote this, I was made aware of two other anti-itching drugs that I was not aware of. I have no experience with them, but I thought I would list them here:
Nalfurafine a K-opioid-receptor agonist which is approved in Japanย (2009) and South Korea (2013).
ย Nalbuphine, a mixed k-opioid-receptor agonist and partial-opioid antagonist. It has central nervous system effects and may cause dysphoria. It has abuse potential, though it was initially a schedule II drug, it no longer is.
COI: I was a site PI for KALM-1. I recorded a video testimonial for difelikefalin a few years ago. I have attended an advisory board with Cara, the company who developed the drug. I have participated in these because I have seen the product relieve suffering. I would not support a product I did not believe in.
USRDS tracks the eGFR of patients starting dialysis, and from the mid 90s through the first decade of the 21st century there was a steady increase in the average GFR at the initiation of dialysis.
While the trend began before 1999, I suspect that the introduction and widespread adoption of the MDRD formula, which revealed that older people with relatively modest increases in creatinine had profoundly low GFRs, had a role in this. This recognition was further reinforced when KDOQI introduced the CKD stages in 2001 that called CKD Stage 5, “Kidney Failure” and implied that CKD stage 5 was a synonym for dialysis.
The trend of starting dialysis at earlier and earlier GFRs reversed following the publication of the IDEAL Trial in 2010. IDEAL showed no survival advantage for starting dialysis at a specific GFR compared to waiting for uremic symptoms that forced the patients to start dialysis. Dialysis is not a cosmetic procedure, we only do it when it is essential.
But deciding when to initiate dialysis is not as easy as waiting for a patient to become uremic, because guidelines, based on retrospective data, tell us to avoid central venous catheters and place arteriovenous access for hemodialysis. Grafts are pretty easy because they usually mature and are ready to use in less than a month. Fistulas, on the other hand, take time to mature and often fail to mature at all.
In this RCT of clopidogrel to assist in access maturation, two thirds of all fistulas were deemed inadequate five months after placement. A few more may have matured after that, but I don’t think it is likely and with a patient nearing dialysis, I suspect new plans for an alternative access will be sought out by that time.
So planning for hemodialysis, with a fistula really means trying to predict where a patient will be six in the future. Learning to do this is the art of taking care of patients with advanced CKD. During my career I have repeatedly been surprised by how long patients with advanced CKD can hold off and delay dialysis. Every time these patients come in I would bring up a list of their old GFRs and marvel how long they had been going with a sub-20 ml/min GFR. Often this would stretch for close to a decade. So when Navdeep Tangripublished his Kidney Failure Risk Equation (KFRE) I felt validated as it showed that patients with low GFRs avoided dialysis longer than doctors (and patients) expected.
How the Kidney Failure Risk Equation (KFRE), physicians, and patients did at predicting the initiation of dialysis. Below the line of identity means over predicting dialysis, over the line of identity is under predicting.
On Wednesday I posted a typical case to twitter and asked people to decide between sending the patient for fistula creation now or to wait. It is the same patient in both polls, but in the first I provided the eGFR, while in the second I provided the KFRE result.
Same patient; wildly different results. I think it does a nice job of showing that people underestimate patients’ prognosis when they look at eGFR. I find I use the KFRE when talking with patients all the time. It helps reassure people with good kidney function when they are first diagnosed with kidney disease and it helps me when they have advanced CKD when trying to figure out the timing of access procedures and more detailed discussions of end-stage kidney disease.
This web app by Amarnath Marthi allows you to play with the variables in nearly real time to get an idea of how the equation works (though I wished it would let me use mg albumin / g creatinine). Note that the risk of ESRD goes down as the patient’s age goes up. This is due to the competing risk of death becoming larger with advancing age.
Below are links to some of the great tweets that emerged from these posts. It always amazes me the breadth and depth of knowledge I find in my Twitter feed.
If a "good" 80 would send for AVF now, if fair to frail would start HD trial with CVC when the time hits
There is missing information – what was his rate of progression to date? , does he have comorbidities? A scoring system makes a mockery of the clinicians ability to individualize care for the person in front of him. Do betterโฆ
When death & dialysis are competing risk factors, the rate of GFR decline is so critical in making AV access decisions. This patientโs GFR loss is 1-3 ml/min/year so will hold off on AVF placement. If he reaches ESKD in 4-5 years (at age 85) proceed with AVG
Fistula candidate means just that. Many other variables need to be accounted for to get a functioning fistula.
How about taking into account the data that creating an avf can slow down renal fx decline. Articles by Tom Golper from Vanderbilt and some others. Would that change the plan https://t.co/MKIHtno07i
Was not aware of this data, though it seems a bit soft. But if it pans out, it would be practice changing, at least for me.
So this 80 yr old patient with gfr of 14 has only 31% probability of needing dialysis at 5 yrs?? That seems pretty low. Not sure the equation remains validated well at this age group.
This last tweet is here because in my reply I post a reference that shows that the KFRE actually cover estimates need for dialysis in the elderly not underestimates.
I had the opportunity to give grand rounds at Ascension St John hospital, my home institution, last week on the new CKD-EPI equation that calculates eGFR without a race modifier.
PowerPoint:New eGFRequations! Now with less racism (69 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.
