What does renal denervation mean for the future?

Symplicity HTN-2 just published its one-year results. The results are just as impressive as the 6-months results. Symplicity 2 is the first randomized controlled trial of radiofrequency denervation. The technique (described here) uses a catheter to deliver radiofrequency energy to the renal arteries. This denervates the kidneys and decreases sympathetic inflow. The lack of sympathetic stimulation reduces renin and peripheral norepinephrine levels which serve to decrease the blood pressure. The study enrolled patients with resistant hypertension, i.e. uncontrolled blood pressure despite compliance with three anti-hypertensive medications including a diuretic.

The primary end-point was change in office blood pressure at 6 months. An average of 30 mmHg drop in patients with resistant hypertension is incredible!

After the primary end-point, patients randomized to the control group had the option of receiving the procedure and their data is also presented in this update.

In addition to the average drops in blood pressure, the benefits were widespread with 83.7% having a lower systolic BP at 6 months and 78.7% at 12 months.

There was not a statistical difference in number of blood pressure medications used at the end of the trial (see table 5 below) but the results are tantalizing and I believe represent a Type II error. This should be an interesting outcome to keep an eye in the forthcoming Symplicity HTN-3 trial.

The procedure appeared safe with 1 episode of renal artery dissection in the cross-over group and one episode of hypotension following procedure that responded to conventional treatment. There was 1 dissection in the 153 patients in Symplicity HTN-1.

The procedure was without complication in 97% of patients (149 of 153 patients). One patient experienced the renal artery dissection on placement of the treatment catheter before RF energy delivery was delivered in that artery. The dissection was treated with renal artery stenting without any subsequent complication or delay in hospital discharge. Three other patients developed a pseudoaneurysm/ hematoma in the femoral access site; all had had an 8F guide and were treated without any subsequent complication.

This data is consistent with the Symplicity-1 results which, though non-randomized, showed a durable anti-hypertensive effect through 3 years.

Symplicity-3 is currently recruiting. It is also a randomized controlled trial but it is twice the size of Symplicity HTN-2. Additionally it uses 24-hour ambulatory blood pressures rather than office pressures to measure efficacy.
This looks like an effective therapy and of course we will have to wait until it is approved for wider use but it is hard to look at this technique and see anything but a game-changer. We are looking at a non-pharmacologic therapy for hypertension that does not require medical compliance. Imagine cardiologists, instead of boxing the kidneys with drive-by renal angiograms, actually helping the patient by lowering their blood pressure. Cardiologists helping the kidney, difficult to wrap my brain around that. Brave new world indeed.

Kidney International, you may want to look at your podcasts.

I spend half an hour commuting to work everyday and usually listen to podcasts. My tastes mostly satisfy my unnatural Apple cravings. I listen to a lot of 5×5, TWiT and Slate podcasts, but recently I subscribed to a handful of Kidney podcasts.

I was listening to the Kidney International Podcast and they start interviewing (iTunes Link) Barry Freedman of Wake Forrest. He starts talking about the MYH9 gene. This tweaks my interest and I start paying attention, thinking to myself, “Is this gene making a comeback?” And then he starts talking about the the Nature Genetics papers from 2008. No mention of APOL1. I glance down at my iPhone, the podcast is from 2009. I was relieved that I hadn’t missed a major U-turn. Listenning to the remainder on the podcast I can’t help but smirk at the hyperbole.

His paper was on hypertension associated end-stage renal disease and its tight association with MYH9. He waxes on about how it is one of the most strongly associated genes in any common disease. He states that if you could remove the MYH9 risk variants from the African American population, 70% of the non-diabetic kidney disease would disappear. He states that MYH9 is responsible for initiating most kidney disease in African Americans and that hypertension is very unlikely to be an initiating factor in kidney disease.

If you are not familiar with the history of this wrong-turn, here is a brief overview:

  • In October 2008, Jeff Kopp, using a new technology known as admixture-mapping linkage-disequilibrium genome scan found an association with FSGS and a variant in the a gene called MYH9. The same gene variant was also associated with HIVAN. This was hailed as a major break-through explaining the excess kidney disease burden found in African Americans.
  • MYH9 had already been associated with a cohort of genetic conditions that all had glomerular pathology so the link seemed pathophysiologically sound.
  • The nephrology research world became fascinated with this gene and for about a year tremendous resources were focussed on this gene.
  • In July 2010, Science published data that showing that a different gene, APOL1, located close to MYH9 on the chromosome, was actually responsible for the high association of disease. Of note Barry Freedman is also an author of this paper.
  • Being heterozygous for APOL1 is protective against the Trypanosoma parasites that cause African Sleeping sickness
    • Trypanosoma brucei brucei infects many mammals but is unable to infect humans because human serum contains a complex, trypanosome lytic factor (TLF)
    • Trypanosoma brucei rhodesiense and Trypanosoma gambiense evolved a defense against TLF and were able to infect humans.
    • A single copy of APOL1 restores TLF and makes the carrier immune to sleeping sickness
    • Two copies of the APOL1 predisposes the carrier to proteinuric kidney disease and HIVAN
    • Balanced polymorphism
    • APOL1 mutation is about 10,000 years old, but humans migrated to Europe 70,000 years ago, so Europeans, never shared in the mutation.
A more thorough rehash can be seen in my Dialysis for the Internist lecture (KeynotePDF).
While it is hilarious to listen to the certainty of Dr. Freedman’s proclamations, the incident also has a lesson for dealing with social media. Publishers, including bloggers, are constantly publishing information that expires. Facts become falsehoods and time reveals truths. However, what we have published remains. Leaving these mistakes, without editorial comment is a disservice to our readers. Even though what we wrote may be buried under dozens of posts, Google still indexes it and still sends readers to this material. Kidney International unfortunately never did another podcast, so when one subscribes to their podcast, this story is what is downloaded as “most recent.” 
Search and the permanence of internet means that we need to take responsibility for old content, in a way that wasn’t necessary in the past.

Grand Rounds: Social and Health Care

On Tuesday December 4, I will be presenting grand rounds for St John Hospital and Medical Center. This page has the references, lecture notes and a copy of the slides.

PDF of the slide deck (17.3 MB)

One of the gimmicks of the talk was that a scheduled tweets to drop during the presentation. I also peppered my tweet stream with my talk’s hashtag in the 2 days leading up to the talk. This resulted in a nice little buzz of social activity. Looking over the hashtag (#SJHMCsmhc) a day later I found 20 retweets, 14 replies, 11 favorites. This was spread-out over 17 different tweets All way above normal activity for @kidney_boy.

This only captures activity with the hashtag #SJHMCsmhc

I used HootSuite to schedule the tweets.

Notes and References

Picture of Me and Bud
    1. Shame on You… Facebook page
    2. Preemie Primer post by Dr. Jen Gunter the queen of OB/GYN on Twitter
    3. Forbes blog post, Is KV Pharma Evil?
    4. Eli Reschef, OB/GYN leading charge agains Makena pricing
    5. Academic OB/GYN on the Makena Controversy