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 don’t 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…
I’m in the taxi leaving #NKFClinical (or at least I was when I started writing this) and if it wasn’t 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. I’m 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 wasn’t 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 Japan (2009) and South Korea (2013).
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.
