AASK: a cautionary tale for bardoxolone?

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.

Brilliant little video on exercise

My pithy little push for exercise is that it is the closest thing we have found to the fountain of youth. That it doesn’t mater what disease you look at, increasing you exercise or fitness is associated with better outcomes.

Love this video.

Less medicine, better care

Thought provoking article at Zocalo Public Square by Ken Murray a family practice doctor who writes that he was so frustrated with futile end-of-life care he suspended his hospital practice.

Of course, doctors don’t want to die; they want to live. But they know enough about modern medicine to know its limits. And they know enough about death to know what all people fear most: dying in pain, and dying alone.

The essay feels right but relies on anecdote rather than data to support the central premise that doctors are more likely to to use hospice and palliative care to have gentler passing.

Diabetic nephropathy

I was invited to do grand-rounds at St John and was given no guidance on selecting my topic. I recently received a phone call from a long-time family friend, this man had literally changed my diapers, and he asked me to help a relative get bardoxolone. My group is participating in Beacon (the current phase II trial for bardoxolone) and though I am not one of the investigators I assured him that we would evaluate his friend. I couldn’t guarantee he would get study drug rather than placebo or even qualify for the trial.

The whole event shocked me. I had no idea that the results of the Bardoxolone study had slipped beyond the geek fringes of nephrology. It reminded me of a story that Judah Folkman told. He came to Indiana University to collect an award and give a lecture, shortly after a NYTimes profile. In that front page story James Watson (yes that James Watson) said Folkman would cure cancer in two years.

Judah told the story that he was getting phone calls from strangers and friends asking for his miracle cure and was heart broken because he had nothing to offer them. At that stage his drug was only for mice.

That’s Judah and me following the afore mentioned lecture in 1999.

Getting that call from my friend gave me the same sort of Folkman moment. I never thought people would be calling me trying to get experimental therpy. So I decided to talk about Bardoxolone.

As I started my research I became concerned that patients randomized to bardoxolone developed increased albumniuria.

Some patients tripled their albuminuria! The drug increased GFR, but the increased albuminuria could not be fully accounted for by the improved function.
ASN Kidney Week fell 10 days prior to my Grand Rounds so I planned on grabbing some good ideas at the meeting. On Friday I went to Kidney Disease in Type 2 Diabetes: New Insights. There were four lectures. The last two were homeruns.
Dr. Bruce Perkins was perfect for my talk. He spoke of how albuminuria is not a great surrogate end-point for diabteic nephropathy studies. Bad outcomes often follow a reduction in proteinuria.
I used my iPhone to record the audio and took pictures of each slide with my Nikon (this was before I learned that ASN did not want attendees taking pics of the lectures. WTF). When I got home I grabbed the best thoughts from his lecture and made it the cornerstone of my talk on diabetic nephropathy, bardoxolone, and a more modern view of albuminuria.
Thanks Dr. Perkins.

The lecture was a little light, I finished in 45 minutes and used some filler from my Diabetic Nephropathy 2009 lecture. Before I use the lecture again I would add some of the points from Andrew Bomback’s excellent lecture, “RAAS Blockade: More is better? Yes. No. It depends.”

Here is my PowerPoint (58mb) and PDF (51mb).
Note to self: the Helvetica Neue UltraLight, didn’t project so well.

We’ve got one! Finding a functional adrenal adenoma

A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.

The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.

One of the findings that stood out for me was the hypokalemia on the initial labs

We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was “real” and after that she was compliant with the medical therapy.

The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:

Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.

Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.

The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt

An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:
  • aldosterone in nanograms per deciliter
  • renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour
With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn’t meet the criteria for primary aldosterone is not important to me because I’m going to treat both of those conditions identically, with spironolactone or eplerenone.

So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.

Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:

Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.

The authors did not provide a 2×2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:

  • Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
  • Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
  • Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives
The two-way table looks like this:
What? You’re still using Epocrates’ medical
calculator? Don’t be a tool, get a tool, MedCalc
It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.

We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.

She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.

The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.

And the data keeps rolling in…

I am a believer in Richard Johnson’s theory regarding fructose uric acid and hypertension/CKD. So I love it when I see another study adding to the foundation. This from Diabetes Care. The investigators looked at 1500 patients with diabetes and normal renal function and no proteinuria. Over 5 years they tracked who developed CKD (either GFR<60 or proteinuria):

During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD.

Write your own text book, save money

I bet this becomes a real trend as school districts become short for cash.

Anoka-Hennepin teachers write their own online textbook, save district $175,000

Instead of mass-produced textbooks, the more than 3,100 sophomores in the state’s largest district are learning from an online curriculum developed by their teachers over the summer with free software distributed over the web.

 For the extravagant tuition charged at medical schools it seems they should throw in the course materials for free. No?