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NSAID alert! or not.

The news wires lit up last week with the revelation that ibuprofen can cause acute renal failure and it even can happen in children. 
MD Mama
CBC News Health
Everyday Health
Counsel and Heal
MedPage Today
NewsMedical.Net
EmaxHealth
My favorite tweet on this came from pediatric nephrologist, Pascale Lane:

“@asnkidney: Could NSAIDs contribute to an increased risk for acute kidney injury in children? bit.ly/14hBifN” Yes. Next question
— Pascale Lane (@PHLane) January 26, 2013


The publicity department of Indiana University must be quite pleased with themselves with the wide coverage this study has produced but behind the curtain we really have very little data. The study was published in J Peds (Abstract | PDF). The authors did a retrospective chart review of 11.5 years of inpatient records from Riley Children’s Hospital in Indianapolis. They found 1,015 patients with acute renal failure by screening ICD-9 codes. This is a shockingly low frequency to me. Eighty-eight cases a year in a major children’s teaching hospital makes me think theire screening methodology was quite insensitive.
The authors did not comment on how accurate the ICD-9 screening methodology was. They said they examined all of the charts but didn’t mention if any of the cases were excluded after examination because of a lack of acute renal failure. This also seems unlikely, as many patients with chronic kidney disease are initially coded as acute renal failure. It would have been nice to get a sense of how specific the ICD9 screening methodology was, even if they couldn’t comment on the sensitivity. (Update, this article looking at AKI in adults states that ICD9 codes have a sensitivity of 28% and specificity of 99%)
Having amassed this trove of acute renal failure data the authors did not report on acute renal failure in general (hopefully a future paper will elaborate on this. I would love to see comprehensive data on the epidemiology of pediatric acute kidney injury, something like The Madrid Acute Renal Failure Project) and instead did a deep dive on NSAIDs. Here is the breakdown of etiologies of acute kidney injury in this study:
Co-morbid conditions were defined as: malignancy, complex congenital heart disease, sickle cell disease, etc.
Alternate diagnosis were defined as:obstruction, hemolytic uremic syndrome, pyelonephritis, sepsis, transplant rejection, or glomerulonephritis.
I have pulled out the two slivers which represent the NSAID associated renal failure. The ignored elephant in the room, is the absence of pre-renal azotemia in the lists of diagnosis. This has previously reported to be the most common cause of kidney failure in patients presenting with ARF and the second most common in hospital acquired ARF (Madrid ARF study | PDF). The authors had little to say about volume deficiency as it pertained to the etiologies of renal failure. This what I could find:

Although volume depletion is an independent risk factor for AKI, patients with a history of volume depletion in the absence of sepsis or multiorgan failure were not excluded from classification as having NSAID-associated AKI, as it is likely that volume depletion increases the risk of NSAID use leading to AKI.

The authors had this to say about the frequency of NSAID induced ARF:

Our study is the largest series to date demonstrating that NSAIDs are a common cause of AKI in children.

I read that statement and look at the pie chart and then look at results that show 27 cases of AKI over 12 years and I must say, I’m not impressed.
The authors try to pump up the frequency by expanding their definition of NSAID induced AKI:

However, it should be noted that in our population, many patients who were deemed to have developed multifactorial AKI (and thus were not included in the case definition of NSAID-associated AKI) did have NSAID exposure as one of their multiple risk factors for AKI.

This feels disingenuous. If you create the case definition, don’t try to spin your results by essentially saying, if we had a different, less specific, case definition we would have found more cases.

Of note: the authors found that 44% of the cases were above the 95% for height:weight or BMI. The authors tried to see if this was due to NSAID overdose because of parents dosing kids by actual rather than ideal weight. This was not the case. However this is consistent with the recent results about adiposity being related to AKI in trauma patients. Obesity, an independent risk factor for AKI. Neat.

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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.
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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 (Keynote, PDF).
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.
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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

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Weight loss and CKD, one patient’s experience.

I just discharged a patient from my CKD clinic. I first saw her in the CKD clinic in 2008. When she presented she had CKD stage 3/4 (eGFR of 30 mL/min) with a creatinine of 1.8. I was very concerned about her risk of progression to ESRD due to three elements from her history:

  1. Recent episode of ARF following a UTI. We know now that AKI is a risk factor CKD progression, especially in diabetics, but even 5 years ago I used it as a personal bias flagging patients with scant renal reserve and fragile kidneys.
  2. She had previously had a nephrectomy for renal cell carcinoma. I always worry about these patients getting hyperfiltration injury, though in my experience this is rare and they generally do much better than their peers with equally diminished GFRs.
  3. She had a BMI of 45, which also increasing her risk of hyperfiltration injury.
Image via Methodist Hospital

On her first visit, she asked if losing weight would help her kidney disease. I told her that I felt it would. She had already tried a variety of diet and exercise programs and had repeatedly failed. Over the ensuing year we discussed weight loss options and ultimately she consulted with a bariatric surgeon. In February 2009 she went for a laproscopic gastric band procedure.

Since that procedure she has lost 132 pounds. Her hemoglobin A1c has gone down from 9.9 to 5.7 in the face of stopping insulin and her three oral hypoglycemics. But the most remarkable thing for me has been the way her creatinine has melted away from 1.8 to 0.7. Her microalbuminuria went from 139 to 3 mg/g creatinine. She went from CKD 3/4 to CKD 1.

JASN recently published a report by Turgeon, showing increasing complications with bariatric weight loss procedures in patients with chronic kidney disease.

In a 2009 meta-analysis, Navaneethan found that bariatric surgery reduced proteinuria, blood pressure and GFR. The reduction in GFR was not in CKD patients and really relfected a normalization of hyper-filtration from a GFR of 140 to 117 mL/min.

Risks occur with bariatric surgery, as shown in Turgeon’s study. In addition to the short term surgical complications, AKI, rhabdomyolysis, hyperoxaluria and kidney stones all can occur after weight loss surgery. An additional wild card in assessing how CKD patients do after surgery is the fact that using the MDRD in the morbidly obese is uncertain. Perhaps my patient’s improvement is due simply to increased accuracy of the MDRD equation as her BMI approached a more typical level. That said, given the reduction in her albuminuria, the apparent curing of her type two diabetes and her remarkable fall in creatinine I feel she has truly benefitted from the surgery.
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FENa and FEUrea revisited

At Renal Week I went to Mark Perazella’s talk on “Urine Microscopy for Diagnosis and Prognosis in Hospital-acquired AKI.” Perazella published the interesting paper in CJASN in 2008 on using urinalysis microscopy for prognosis. His talk focused on the same subject. The gist is that a trained observer of urine microscopy is not only more accurate at diagnosing the etiology than FENa and FEurea but can provide prognostic information. Additionally, urine microscopy performs as well as the novel biomarkers: KIM-1, NGAL and IL-18.

As part of his talk Perazella threw-up some slides with some surprising statistics on the diagnostic utility of FEUrea and FENa:

From Pepin AJKD 2007: 50:566-573

A sensitivity of 48% without diuretics? A specificity of 33% with diuretics? Terrible. A second study showed similarly terrible numbers:

From Darmon et al. Critical Care 2011: 15 R178.

Only a bit better than a coin toss.

I felt shamed. I had been teaching and using urinary acute renal failure indices for 20 years and to see that they sucked sucked, kinda hurt. But then as I thought about it, I remembered seeing primary data that was quite a bit more compelling. So I went back to the primary literature.

The fractional excretion of sodium was invented in 1976 by Carlos Hugo Espinel. His initial series was published in JAMA. In that study he found 100% sensitivity and specificity in 17 oliguric patients.

Holy shit! Shrier is a member of the
Indiana Basketball Hall of Fame!

The study that is usually referenced as the mother of the fractional excretion of sodium comes from Mr. Sodium himself, Robert Schrier (fun fact: the founding member of my practice, Joseph Beals, was college roomates with Robert Schrier). This group found excellent performance of FENa in 85 patients:

Dr. Kohn is in the middle

FEUrea was invented by Kaplan and Kohn in 1992 (Fun fact: Dr. Kohn was one of my professors at University of Chicago) but the technique was not validated until 2002 when Cavounis et al prospectively looked at 102 patients with AKI. I remember reviewing the Cavounis article in journal club with Dr. Kohn in the room.

Results for using FENa to diagnose pre-renal disease (<1%)

  • 92% sensitivity without diuretics
  • 48% sensitivity with diuretics
  • 76% sensitivity for the entire cohort

Results for FEUrea to diagnose pre-renal disease (<35%)

  • 90% sensitivity without diuretics
  • 88% sensitivity with diuretics
  • 89% sensitivity for the entire cohort

Kim et al looked at 107 patients with acute kidney injury. Instead of pre-renal versus ATN they used transient versus persistent. They also looked at the performance of the AKI indices in the context of diuretics. (disclosure, I just read the abstract)

Results for using FENa to diagnose pre-renal disease (<1%)

  • 96% sensitivity 100% specificity without diuretics
  • 63% sensitivity 98% specificity with diuretics

Results for FEUrea to diagnose pre-renal disease (<30%)

  • 92% sensitivity 87% specificity without diuretics
  • 96% sensitivity 83% specificity with diuretics

Diskin et al looked at 100 oliguric patients and evaluated FENa and FEUrea. They used 40% for the line with FEUrea and 1% for FENa.

  • FENa 54% sensitivity
  • FEUrea 95% sensitivity
This was all the data I could find on trials that look at FENa and FEUrea. Overall, it performed quite well in most studies. In fact the two trials that Perazella quoted were the only two with the indices embarrassing themselves.
Jonathon Gotfried’s article in the Cleveland Clinic Journal was a great resource for this article.

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Shame on you US News and World Report

So I was browsing my twitter feed yesterday and saw this from @okarol

One perspective on the proposed changes to how the distribute kidneys fb.me/100dAwkxi
— Karol Franks (@okarol) November 12, 2012

Then I saw almost the exact same message was on my Facebook feed from The Kidney Group:

Twitter’s most followed Kidney Practice: the kidney group should be ashamed of this post.

Both posts point to the same article in US News and World Report about the proposed change to the transplant guidelines and describes the change as unethical.

To understand what is driving the desire to change the current system and to understand how the proposed system is superior, one needs to understand the shortcomings of the current way organs are distributed.

First, unlike hearts or livers, people can live for years on dialysis waiting for a transplant. This is why we have 75,000 people on the kidney transplant list. Tragically, only 16,843 were transplanted in 2010.

Look at the 15,000 people listed for
the second or third time (USRDS)

Currently the most common reason for a kidney transplant to fail is death with a functioning graft. On the one hand, death with a functioning graft is an ideal outcome, this is how the vast majority of people without kidney disease die, i.e. they die with a kidney still capable of supporting life. But in the world of kidney transplant, death with a functioning graft is a measure of inefficiency. We live in a world with a vast undersupply of organs and not only are there not enough organs to go around, but an increasingly common reason for patients to be listed for a transplant is re-listing after their first transplant failed. If all of these patients had been matched to a kidney that better lined up with their life-expectency they would not be getting back in, an already overcrowded, line.

Over time total graft failure and return to dialysis/transplant has fallen but death with a functional graft has remained flat. Better graft matching could mean more people living with transplants. (USRDS)

Another problem with the current list is how wait-time is calculated. Currently time on the list starts from the time a patient is approved for a transplant. This seems fair until you see who is not getting referrals to transplant. There is data that shows that patients dialyzed in commercial dialysis facilities (the vast-majority of dialysis patients) are less likely to get referred for transplant. Other studies have pointed to minorities and patients without commercial insurance being less likely to be referred for transplant.

Michigan no longer uses that system for calculating wait-time. In Michigan, the clock starts the first day of dialysis. So a dialysis patient that takes three years to finally find his way to a transplant center and get listed would get credit for three years of wait time as soon as he was approved for transplant. This largely neutralizes any discrimination he would have suffered from being randomized to a bone-head nephrologist or living in a racist medical system. This is a smart change and it is used by the proposed transplant allocation system.

The current system is over 25 years old and suffers from limited medical knowledge available at the time it was created. The current system looks at factors that affect graft survival (HLA matching) but ignores factors associated with recipient survival (diabetes, age, etc).

We grade patients antibody levels (PRA) on a continuous scale from 1 to 100. Patients with higher levels have more difficulty finding matches. In order to help these patients with additional burdens in finding a match they are awarded points. Unfortunately the current system awards a fixed value if the level is over 80 and does not appreciate the continuous nature of this factor. The proposed system treats this as the continuous value it is.

Currently, there are a lot of discarded kidneys that could be used to benefit patients but the current system ranks kidneys as Standard Criteria or Extended Criteria. A system that recognized that not all recipients need 20 years of renal function would allow more of these marginal kidneys to be used.

It is interesting that Laine Ross’s article does not address any of the weaknesses of the current system. The reader is left with the impression that the current system is fine except for a vague mention of “inefficiencies.” She does not elaborate on what inefficiencies means but, make no mistake, it means we can get more people living with a transplant by changing how we allocate the organs. The new system plans on doing that, so if you agree with Laine you are arguing for less people living with a transplant.

The centerpiece of the proposed system is a system that ranks both recipients and the kidneys. The top 20% of candidates (by estimated years of life remaining) are matched to the top 20% of kidneys. Getting young people high quality kidneys that will last decades makes sense to me but apparently ethicists from the University of Chicago feel that putting 20 year old kidneys in 68 year old diabetics is a good use of a scarce resource. By giving young people long lasting kidneys we can avoid these patients losing their kidneys and getting re-listed. This will help reduce the total wait list.

The rank list also works on the bottom end of the scale, acceptable but marginal kidneys at the bottom of the scale, the worst 15%, are made available to patients on a voluntary basis. Older patients and patients who are failing dialysis can be desperate for a kidney. This is intended to expand the project that began with extended criteria donors and reduce the number of viable kidneys that are wasted.

Outside of the top 20% and the bottom 15% the system does not change. This new allocation is really just a revision to update and fix some weaknesses with the current system.

Ross calls out the 20% rule because it can not magically determine the exact time of death of everyone in the queue for a transplant. Seems like a pretty high bar to cross. The system that is proposed has a c-statistic of 0.72, which is where she get’s her:

…their model will get it right about 75 percent of the time.

The system is just as accurate as the system used to determine life expectancy for liver transplants and does a very good job of preventing the primary problem of putting kidneys with a short life expectancy in patients with a long life expectancy. The system does not need to be perfect to be better than the current system which is totally blind to this important issue. Interestingly, the Kidney Committee, looked at a better system to predict life-expectancy but it was so complex that people were suspicious. They settled on the current system because it is simple and does a good enough job. I agree that transparency is an important quality in any system that will be distributing kidneys.

Reading the whole article it looks like a hit-peice trying to score ethical points while lives hangs in the balance. This is the third attempt to revise the transplant allocation program. Ethicists have repeatedly deep six-ed previous attempts and while we try to find the perfect system we are trapped in a system that everyone agrees has significant ethical lapses and wastes both kidneys and years of transplant viability.

Update: The Kidney Group has removed the link to the article from their Facebook page. @okarol has blocked me on Twitter. No peep from U.S. News and World Report. This post made it to the RenalWEB homepage.

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Do we need to EVOLVE our views on EBM in dialysis

I have posted on the release of the EVOLVE data at Kidney Week 2012 at the eAJKD blog.

This is a big deal and when I read the @NEJM tweet it makes me mad.

Cinacalcet doesn’t lower death or major CV event risks in patients undergoing dialysis. nej.md/U4yeSv #kidneywk12
— NEJM (@NEJM) November 3, 2012

That tweet provides only the first sentence in what should be an important and longer discussion of the findings of EVOLVE. To completely discount EVOLVE as @fish2phil and @Nephroboy do…

@kidney_boy these are statistical machinations attempting to squeeze a diamond out of coal.
— Homer W. Smith (@fish2phil) November 4, 2012

It’s cack. “@kidney_boy: My first take on EVOLVE: biggest, longest, RCT ever undertaken in dialysis population ajkdblog.org/2012/11/04/kid…“
— Nephroboy (@nephroboy) November 4, 2012

…leaves the nephrologist in a bit of a bind. If we ignore studies that don’t meet their primary endpoint, what are we left with? Here is a list of ALL the randomized controlled trials in dialysis that use hard outcomes. This list ignores any study where the end-point is an improvement in a biochemical parameter, echographic finding, or vital sign:

  1. NCDS from 1981: Positive. We learned that small molecule clearance is better than large molecule clearance
  2. Normalization of hematocrit: Negative. No advantage and nearly significant disadvantage to normalizing the hemoglobin
  3. HEMO: Negative. Definitively negative trial showing that small molecule clearance can not get any better with thrice weekly hemodialysis
  4. ADAMEX Negative. Peritoneal dialysis version of HEMO, same result
  5. AURORA Negative. Statin trial with rosuvastatin
  6. 4D Negative. Statin trial with atorvastatin
  7. SHARP Positive, kind of. Statin plus ezetimibe was able to reduce CV endpoints however they lumped dialysis and CKD patients together. The dialysis patients alone were not powered to find a difference and they did not. I think most nephrologists, in the face of 4D and AURORA are pretty skeptical of this data approach.
  8. DCOR Negative. Trial of sevelamer versus calcium containing binders.
  9. IDEAL Negative. Trial of early versus late initiation of dialysis. No advantage for early start. Some may argue that this is a CKD rather than dialysis study.
  10. EVOLVE. Negative.
Is that it? I can’t think of any others. Nephrology operates in an evidence desert. (Hat tip Dr. Dale)

I’m a nephrologist because I’m comfortable operating in a low evidence environment.#FaithBasedSpecialty
— Joel Topf (@kidney_boy) November 3, 2012

So if you want to throw EVOLVE away because it didn’t reach statistical significance what are you going to do? The questions that EVOLVE attempted to answer do not go away because the study was negative.

In a few weeks I will start going through the November labs for dozens of patients who trust me to give them the best dialysis care. Some of them will have a PTH over 600 and a calcium over 8.4. What will I do? If I am relying on randomized controlled data I will probably just sit in a corner and cry. I could rely on Block’s, Floege’s and Kalantar-Zedah’s data that ties increased PTH with increased risk of death. All of that data is, of course, controlled for age the sin for which Homer Smith is pounding the EVOLVE crew for:

@kidney_boy …not only adjusting for age, but may really be adjusting for important unmeasured covariates that correlate with age.
— Homer W. Smith (@fish2phil) November 5, 2012

Of course if you accept the data that elevated PTH is bad, none of the observational data provides any guidance on what happens when you lower PTH.

To see what happens when you lower the PTH we need to look at the data from the mortality studies done with paricalcitol (Zemplar) and doxercalciferol (Hecterol).*

* The reason there is no link to those studies is that those studies don’t exist. Thanks Abbott. Thanks Genzyme. I have heard rumors of a Zemplar trial conducted in the 90’s but the data was never published and the study buried in the bad old days before trials.gov.

So what is the EBM dedicated nephrologist to do?
I bet if the skeptical nephrologist went to his dialysis patients and explaned to them:

USRDS 2012 Annual Data Report
  • Dialysis patients have a 3 year survival of 50%.
  • There is a drug that is already approved (i.e. not experimental) that recently has been shown to have an 89% chance of being able to reduce mortality by 17%

That every one of his patients would beg for the drug.

Final thoughts: The first time I heard about intention to treat was during the HIV epidemic. Some of drugs were so toxic, especially in the early days of HAART when patients were taking handfuls of pills, that significant number of patients weren’t able to tolerate them. I remember an ID doc expressing frustration that he needed to know if the drug would save the lives of the patients he had that could tolerate the drug. If they can’t tolerate it, he was going to stop the drug, but if they could tolerate it he needed to know if it slowed the virus. In the middle of the epidemic, there is no room for statistical purity.

Like that ID doctor, I want to know if the drug will work if the patient actually swallows the pill, and the answer to that is a definitive “Yes.” Hazard ratio for death of 0.83 P=0.009.

Disclosures: I was a principle investigator in EVOLVE, that means my practice was paid to recruit, and administer a bitch of a study that lasted longer than it was supposed to. It was a lot of work, a lot of meetings, a lot of signatures, a lot of responsibility, and not so much money. My name will not be among the authors.

My name on page 53 on the supplement
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Reata, a no show at ASN Kidney Week

What do you do when your tentpole molecule fails it’s phase three clinical trial? I guess you don’t even build your booth at Renal Week.

At Kidney Week 2010 in Denver, Reata presented the results of BEAM, the phase II trial of bardoxolone as part of the late breaking clinical trial data. They shocked the world by showing increased GFR in diabetic nephropathy. The data was published in the NEJM in July 2011. But even before publishing they began work on the phase III trial, BEACON.

I can attest to the excitement that BEACON generated. I was not an investigator but I did enroll one patient in the trial and even had friends calling me trying to get loved ones in the trial. I outlined my experience with bardoxolone in the diabetic nephropathy talk that I gave to the Michigan State Medical Society (Keynote | PDF). On October 18th, Reata terminated BEACON due to “excess serious adverse events and mortality.”

Unfortunately, October 18th was only 2 weeks before the Start of KidneyWeek 2012, the premier nephrology conference in the U.S. Reata had already signed on with the American Society of Nephrology to be a Diamond Level Sponsor:

Not only were they a Diamond Sponsor, but they had bought top billing on the Abstract Book with a full page ad on the back cover:

The ad implores you join them at booth 1529. I went by there just to see how the company would try to spin this disaster. But there was no booth 1529. The map shows it between Amgen and Otsuka, but there is just a pharmacy and an EMR company in its place. It’s like the opposite of when Obi-Wan goes to Yoda trying to find the Planet Kamino.


Lost a Planet Master Obi-Wan Has

Poor Reata. Evidence-based medicine can be such a bitch.

I’d show pictures, but taking pictures of the booths is forbidden by ASN policy. Whisky Tango Foxtrot