When 1A evidence is not 1A evidence.

Nephrology Merit Badge for digging deep into CPG

A few weeks ago I posted about using ceftriaxone and ampicillin for enterococcal infective endocarditis. There are a few studies which support this aminoglycoside avoidance and to my eyes it seemed like a reasonable therapeutic option, especially in my patients who are often at high risk of aminoglycoside toxicity. I pinged twitter to see if I was fooling myself into believing what I wanted to believe or if this was a viable therapeutic option.

Hey ID docs, what do you think about treating enterococcus endocarditis without gent?Check out this article:ncbi.nlm.nih.gov/pubmed/23392394
— Joel Topf (@kidney_boy) February 14, 2013

The first responders (of the twitter variety) were the pharmacologists:

@kidney_boy @pharmertoxguy I believe you have all the key trials on this subject including the most recent. Enjoyed the post.
— Timothy Aungst (@TDAungst) February 14, 2013

@kidney_boy Not a lot of data for our old gent stronghold on synergy. Good post. @tdaungst
— Bryan D. Hayes (@PharmERToxGuy) February 14, 2013

Thanks @pharmertoxguy @tdaungstI was looking for RCT of Amp+placebo v Amp+Gent could not find one but Amp+Gent is 1A rec. How?
— Joel Topf (@kidney_boy) February 14, 2013

Then Med student, Alex Michaels, called me out on how my post relied on observational data:

@kidney_boy this seems to go against you’re preaching of EBM. all cited articles in your post are observational non rct vs 1A guidelines?!
— Alex Michaels (@amichaels04) February 14, 2013

I replied with increasing desperation:

@amichaels04 in the absence of RCT this is all we have. It would be great if you can come up with any 1A worthy studies. Couldn’t find any.
— Joel Topf (@kidney_boy) February 14, 2013

Then the always insightful but confrontational Jim Smith weighed in with the conservative point of view:

@kidney_boy do you think evidence is strong enough to defend going against IDSA recs in the event of a poor outcome?
— Jim Smith (@jklm) February 15, 2013

@kidney_boy Yeah, but hindsight is always 20/20. I’m wondering if evid is strong enough to go against what seems to be SOC from outset.
— Jim Smith (@jklm) February 15, 2013

(SOC is standard of care)

@kidney_boy I’m not saying it’s wrong to do/try. But I’d be very interested in opinion of ID experts. Have you heard from any?
— Jim Smith (@jklm) February 15, 2013

This back-and-forth began to crystalize what bothered me most about the ISDA/AHA guidelines, they graded the evidence as 1A but the supporting text did not link to one randomized controlled trial. Up to now I had not received any input from infectious disease experts so I started to fish for them.

@jklm just some pharmDs (the real brains in therapeutics)
— Joel Topf (@kidney_boy) February 15, 2013

@janinemccready @abx_id_doc @drjudystone Could you look at this post and tell me what I got wrong.pbfluids.com/2013/02/aminog…Thanks
— Joel Topf (@kidney_boy) February 15, 2013

Dan Riciuto was the first to get back to me. Here is summary of his 5 tweets (1, 2, 3, 4, 5)

Nice post. Always good to question dogma. I’ll try an get back to you later with a bit more detail. I think enterococcus is actually more difficult to treat than say Staph, though two weeks of gentamicin may be fine. I’ve used ampicillin and ceftriaxone but there is a lot of side effects, fluid and sodium load with the high dose ceftriaxone.

I replied:

The guidelines say amp gent is 1A rec but then they don’t give any refs to support “multiple RCT” to satisfy 1A strength. I also searched UpToDate and they also don’t cite any RCTs, just observational data. Does the emperor have no clothes? (Tweet 1 and 2)

He continued

There are very few RCTs in ID unless it is with a new antibiotic and hardly any in relatively rare conditions like infective endocarditis. Which is why if your read the definition from the guidelines a “Class I: Conditions for which there is evidence, general agreement, or both that a given procedure or treatment is useful and effective.

I replied, that I am not as concerned about the classification (1, 2, 3) but rather the strength of evidence. Why is this recommendation 1A not 1B
He Concluded

@kidney_boy You are right. I will look further, but pretty surenot based on RCT.I’ll email the author.
— Dan Ricciuto (@Abx_ID_Doc) February 16, 2013

Janine McCready also helped out:

@kidney_boy1/6 Thanks for q & nice post. Enterococcal IE harder to treat than other bugs as demo’d by high mortality even with ‘cidal tx.
— Janine McCready (@janinemccready) February 16, 2013

Here is Janine McGready’s full 6 tweet reply reassembled and de-abbreviated. (here are the original tweets for verification of my twitter translation 12, 3, 4, 5, 6):

Thanks for question and nice post. Enterococcal IE is harder to treat than other bugs as demonstrated by the high mortality even with bactericidal treatment. Old studies show 60% failure with penicillin alone, prompting the addition of aminoglycosides. If you have an ampicillin sensitive strain with a low MIC it may be ok to use a shorter course of gentamicin or ampicillin with ceftriaxone. I’ll take a better look at the new study but I have used high dose ampicillin or ampicillin + ceftriaxone with success. The key is getting a bactericidal combination. The rationale for the addition of ceftriaxone (if I understand it correctly) is that it saturates the penicillin binding proteins (pbps) making the combination bactericidal. In my practice it’s always a balancing act and I usually pull the plug on the aminoglycoside after 2 wks and consider substituting ceftriaxone if there is any concern regarding nephrotoxicity or worrisome and irreversible vestibulo/ototoxicity. Sorry the response so is long, hope that helps…

At this point I came to the conclusion that Amp + ceftriaxone is a viable second tier option in patients with aminoglycoside toxicity or high risk for aminoglycoside toxicity. However I felt betrayed by the authors of the AHA/ISDA guidelines. The recommendation for ampicillin and gentamicin appears to be a 1A recommendation.

Here are all of the articles which are referenced in the section on enterococci:

126. streptomycin = gentamicin observation
127. gentamicin dosing observation
128, 129. using duration of symptoms to determine duration of therapy (PubMed 1, PubMed 2) observation
130. Aminoglycoside for only 15 days? observation
131. 5 phenotypes of VRE in vitro
132. linezolid for VRE observation
133. Treating multidrug resistant enerococci, disease model
134. Amp and ceftriaxone, disease model, not human data
135. Amoxicillin and cefotaxime rabbit endocarditis
136. Amp and ceftriaxone observation

That’s it. All observational data or experimental data in animals or disease models. Not a single reference to back up the slew A1 grades found in Tables 9 and 10.

Evidence-Based Scoring System from AHA and ISDA
Infective Endocarditis Guidelines

When I first started investigating this I kept expecting to find an RCT buried in some old journal but now I just think the authors broke the rules. I don’t know if I should feel foolish for trusting the authors of clinical practice guidelines or self-rightous for smoking these jokers out. Is this kind of deception common in CPGs or is this a particularly sloppy guideline. The nephrology guidelines produced by K/DOQI and KDIGO have all been top notch and transparent with the unfortunate lack of data and reliance on expert opinion. I hope the ISDA/AHA is an exception rather than the rule.

Updates from Twitter (where else?):

@kidney_boy great but sad discussion. see emlitofnote.com/2013/01/what-a… by @emlitofnote
— Seth Trueger (@MDaware) February 27, 2013

Link to a nice post, on a JAMA article looking at the reliability of clinical practice guidelines.

Nephrology Merit Badges, an update

Six months ago I proposed nephrology merit badges:

One of the common resident complaints regarding nephrology is that it’s too hard. The nephrologist response to this complaint  is usually to deny the difficulty, because its not hard for the nephrologist. Perhaps that denial is counterproductive, first it’s hard to disrupt a widely held belief that is continually reinforced by the community of medicine, secondly when you deny the difficulty you insult the intelligence of the student struggling with new concepts. Its essentially saying, “Hard? differentiating among the pulmonary renal syndromes is easy, what are you stupid?”

Instead of denying the difficulty we should re-frame the meme. Yes, nephrology is hard and look how cool it is that you mastered these concepts.

Merit badges, or pieces of flare as my fellow interjected, would add levity and encourage residents to tackle deeper concepts.

Since that time a number of residents, fellows and students have earned nephrology merit badges. The concept has evolved a bit as the badges are being awarded to comemorate specific patient encounters rather than general concepts. So it’s still a work in progress. Here is a summary of the badges:

Sodium Ninja. See this post.

Master of Electricity. This badge was awarded to the residents who were able to quickly and professionally handle a shocking situation. A patient in the acute dialysis unit was repeatedly being shocked by her malfunctioning ICD. Every five to ten seconds, BAM another electric boot to the chest. This went on for what seemed like hours, bit was only a few minutes until the residents were able to procure a magnet to place on the chest and reset the ICD.

Sweet as Black Coffee. This badge was awarded to the residents who were able to accuratly diagnose the etiology behind a case of hypoglycemia. The hypoglycemia was due to adrenal insufficiency and once this hormone was properly replaced the patient’s mood improved as much as his glucose did. Seeing him come alive was almost like Gandolph releasing Theoden from Saruman’s control. The name of the badge comes from one of my favorite brain teasers: what has more sugar, lightly sweetened coffee (one teaspoon of sugar) or all the blood in the body? The answer is the coffee:

Hepatorenal Syndrome. This badge was awarded to the residents who successfully guided their patient through the trecherous waters of hepatorenal syndrome. The symbol behind the organs is supposed to be specter of death but may actually be a heavy metal band symbol. I have not been overly impressed with the quality of research which supports the use of midodrine and octreotide in HRS(PubMed1 PubMed2), but there is no doubt in my mind that HRS was nearly universally fatal when I was a resident in the late 90’s and now I have a hard time remembering the last time I saw a patient die of the condition.

Orthostatic Hypotension. This badge is awarded to the residents who successfully managed resistant orthostatic hypotension. Once the patient has failed midodrine, sodium supplements, elevating the head of the bed, florinef, and waist high compression stockings, you are left with pyridostigmine (Mestinon). This cholinesterase inhibitor, used most often in the treatment of myesthenia gravis, can be used in orthostatic hypotension. The other use of pyridostigmine is an organophosphate antidote, hence the joke.

Koch meets Cochrane. This merit badge was created for the team that did the core research on the data backing up the AHA and ISDA recommendations to use ampicillin and gentamicin for enterococcal infective endocarditis. I plan on posting a follow-up on that situation shortly. I love the illiteration of this badge.

Scout Master’s iPad with a full complement of merit badges

All the badges can be downloaded here as a PDF.

Tolvaptan, a cost benefit analysis

I have a patient who is enrolled in the ongoing TEMPO 4:4 trial. This is another randomized placebo controlled trial of tolvaptan similar to the ground breaking Tempo 3:4 released at Kidney Week 2012. The principle differences seem to be, enrolling people with lower kidney function (GFR >30 versus > 60 ml/min in 3:4).

Recently, he told me about one of his 24-hour urine collections that he has to do as part of the study. He made 7.7 liters of urine in twenty-four hours. As I was pulling my chin off the floor, he asked me if I thought he was on placebo. No, probably not. He agreed.

He has been on “study-drug” for over a year and the polyuria is really disruptive. He is getting up 3-4 times a night and now he needs to take naps during the day because he isn’t getting enough sleep at night.

The guy is on 120 mg of study drug/tolvaptan a day, polyuria is going to be inevitable. The conversation then progressed to how much time the drug may give him off dialysis compared to placebo. Here is the back-of-the-envelope calculation we did to determine if the drug was worth the inconvenience.

His mother reached ESRD at age 55, he seems to be doing a bit better than her, possibly due to the ARB, or just due to phenotypic variance, but we used 55 as the target, that gave him roughly a dozen years or tolvaptan. Using the change in GFR from the sensitivity analysis for males you get the following:

He felt that for him the over-under was about 5 years, and since this beat that handily he was satisfied.

The patient saw a draft of this post and consented to the release of this personal health information.

Cool Wikipedia page of the day: Epidemiological transition

Came across this page as I was putting the finishing touches on an editorial on KDIGO. Apparently, epidemiological transition is a way to understand population dynamics and how they change with increasing medical and societal advancement.

The link at the bottom of the post to the milbank.org PDF is wrong. The correct link is here. Tried to fix it but couldn’t figure out how to edit the refs.

When I learn how edit references on Wikipedia then I will be a master of social media.

Aminoglycoside avoidance in enterococci endocarditis

One of the joys of being a clinical nephrologist is convincing the infectious disease consultant to treat enterococcus endocarditis without gentamicin. The Infectious Disease Society and the American Heart Association have this table regarding treatment:

From Baddour LM, et al. Circulation 111 e394-e434; 2005

The article states that enterococci are relatively resistant to penicillin, ampicillin and vancomycin compared to streptococci. The antibiotics are bacteriostatic rather than bactericidal in these species. Adding an aminoglycoside restores the lethal activity of the Beta-lactam antibiotics. Interestingly the cell walls of enterococci are highly impermeable to the aminoglycosides and would require plasma concentrations incompatible with human tolerance but the beta-lactams increase cell wall permeability so lower doses are biologically active.

The recommendations advise 4-6 weeks of therapy with the combination beta-lactam and aminoglycoside, however it references an observational study that showed effective therapy with as little as two weeks of aminoglycoside exposure. This was a report on 5-years worth of endocardititis from Sweden. They had 93 cases of enterococcal endocarditis

  • Native valve infections: 66 cases
    • 54 were cured 
    • median duration of beta-lactam therapy: 42 days
    • median duration of aminoglycoside exposure: 16 days
    • acute valvular surgery: 11
    • relapse 2
    • deaths 10
  • Prosthetic valve endocarditis: 27 cases
    • 21 were cured
    • median duration of beta-lactam therapy: 42 days
    • median duration of aminoglycoside exposure: 15 days
    • acute valvular surgery: 8
    • relapse 1
    • deaths 5
This looks good to my urine stained eyes, it appears that we can comfortably get away with a shorter exposure to gentamicin, but what really caught my eye was this paragraph:
Seven patients without any aminoglycosides, all with good outcomes.
What about avoiding gentamicin altogether?

In 2007 Gavalda published a case series in the Annals of Internal Medicine. He looked at 43 patients with high-level aminoglycoside resistance (HLAR) or renal failure/high risk for renal failure without HLAR. They were treated with ampicillin 2g q4 hours and ceftriaxone 2g q12 hours.

The data was broken down as HLAR and non-HILAR

  • HLAR 21 cases
    • 6 deaths during treatment
  • Non-HILAR 22 cases
    • 6 death during treatment
    • 2 relapse (one patient received the wrong dose of ceftriaxone)
    •  2 death during follow-up
The most recent data comes from the same Spanish group, now with lead author Hidalgo. Published last week they reported on 159 patients treated with ampicillin-ceftriaxone (AC) and compared them to 87 treated with ampicillin-gentamicin (AG). Here are their results from the abstract:

Between AC and AG-treated E. faecalis IE patients, there were no differences in mortality while on antimicrobial treatment (22% vs 21%, P=0.81) or at 3-month follow-up (8% vs 7%, P=0.72), in treatment failure requiring a change in antimicrobials (1% vs 2%, P=0.54), or in relapses (3% vs 4%, P=0.67). However, interruption of antibiotic treatment due to adverse events was much more frequent in AG-treated patients than in those receiving AC (25% vs 1%, P<.001) Conclusions. AC appears as effective as AG for treating EFIE patients and can be used with virtually no risk of renal failure and regardless of the high-level aminoglycoside resistance (HLAR) status of E. faecalis.

I’m going to try this.

Dialysis for cast nephropathy

I love being a clinical nephrologist. One of the great things about the job has been the non-clinical activities that have burrowed their way into my schedule. In the last 12 months I have:

  • Judged resident research day
  • Taught renal physiology to second year medical students (back to the class room for the first time in a decade)
  • Worked on the scientific advisory board for the National Kidney Foundation of Michigan
  • Attended the editorial board meeting of the American Journal Kidney of Kidney Disease
  • Participated in a mock FDA new drug approval meeting
  • Implemented an EMR and patient portal for my practice
These events, in addition to my regular teaching gigs and taking care of patients, keep my work interesting. 
Last week, I had another novel experience. One of my medical school colleagues, who is now a myeloma expert, asked me to review a case and write a letter in support of a request for “compassionate-use” exception for an unapproved dialyzer. He wanted to use the Gambro HCO 1100 dialyzer, the Nimbus 2000 of dialyzers.
What makes the HCO1100 unique is the exceptionally large pore size. Cast nephropathy is the predominant cause of acute renal failure in multiple myeloma. Removing the offending agent, serum free light chains should have an ameliorating effect on the kidney injury. Previously we have used plasmapheresis to treat this, however this is not beneficial. The HCO1100 is able to effectively remove particles with a molecular weight up to 45,000 daltons and Hutchison et al showed that it can actually dialyze free light chains from the serum. Look at the following clearance data from Hutchison:
The second from the last column on the right has the clearance data.
The Gambro CHO1100 is literally orders of magnitude better than the competition. Hutchison looked at clearance data by examining light chains in the discarded dialysate, this avoided confusion from light chains absorbed to the membrane. Absorption removes light chains from the serum but requires frequent replacing the dialyzer.
The same group followed that paper with an uncontrolled case series of patients, all with biopsy-proven, dialysis-dependent, cast nephropathy. Each was treated with the protocol established by the previous paper* and they had excellent results. Nineteen patients received the therapy. Fourteen of them were able to receive uninterrupted chemotherapy and all fourteen recovered renal function (became dialysis independent). The five who had interruptions to their chemo regimen all remained dialysis dependent. The interruptions were all due to infections and all of these patients died during follow up.
Renal recovery in green, renal non-recovery in red.
The most recent data (good coverage here) I’m aware of comes from Heyne et al. They also published on 19 patients with biopsy proven cast nephropathy. All of the patients were treated on the same chemotherapy regimen which was based on bortezo­mib (Velcade) rather than the various regimens used in the Hutchison series. They too, found a 75% renal recovery. I’m waiting for the PDF of the article because of the Springer paywall (grr).
Definitive information on how effective this therapy is should come from the EuLITE trial which is expected to have results this year. Ironic that some of the only RCT data in nephrology will come from the hematologists.
If you are interested in this you should take a look at Amyloid Planet’s excellent post on suffering from Theralite Envy.
* for those interested the dialysis protocol calls for daily 8 hour treatments. They used 2 HCO1100 placed in series to increase the surface are up to about 2 meters squared. They ran the blood flows at 250 ml/min and the dialysate at 500 ml/min. Dialysis was run daily for 5 days then every other day for 12 days then for 6 hours three days a week.
Update: above I mentioned my frustration with the Springer Paywall and four different readers sent me the PDF. Thank-you. Nice to live in a networked world.

Come on ASN, respect your audience.

I am working on a review of electrolyte disorders in geriatric patients. As part of gathering data I found a resource at ASN Online. They have an entire geriatric nephrology textbook that is available as a PDF for members. That looks awesome. They also have the slide sets from the 2009 and 2008 Renal Week post graduate courses on Geriatric Nephrology, subtitled: An Epidemiologic and Clinical Challenge.

I was looking at those slides sets when I came across this clunker by Myron Miller from Johns Hopkins. Here are some of the low-lights:

I swear the camera on my phone does a better job of scanning image that the undergrad he enslaved to do this transfer.

Nothing says you care, like handwriting the reference.
What a hot mess. It’s hard to imagine you could make a 4×2 chart worse than this one. 

These are the worst slides I have seen in a long time. People who sign up for the post grad classes take an additional two-days off of work and stay in a hotel for what is supposed to be the highest quality nephrology education available. Dr. Miller expresses disdain for his audience with his all-caps, poor scanning and hand scrawled notes. ASN, I’d be happy to talk at any of your sessions. Call me. Maybe?

I tweeted about that last slide and got the following response.

@kidney_boy Take the one that you posted & repost after applying the @kidney_boy filter. Curious what you would do.
— Jim Smith (@jklm) January 31, 2013

I didn’t apply the Kidney_boy Filter™ but I did rework and bring up to date my hyponatremia lecture. Here it is in Keynote (25mb) and PDF (12mb). Feel free to download, comment, remix and rework at your discretion.

The lecture is about an hour long.
Credit (along with a link to pbfluids.com) is appreciated.

Update March 20, 2013: I recently received this e-mail

I am a big fan and review your posts frequently. I saw your recent post on Myron Miller’s slides and agree that they are “clunky” without the mastery that you provide in your lectures, pdf, and posts. I will tell you though that Myron (though an Endocrinologist and Gerontologist by trade) is in part responsible for me becoming a Nephrologist as he guided me through my Residency, exposing me to the wonders of renal physiology and fluid and electrolyte issues. His early work on fluid and electrolyte issues was done in the “low tech” days before IRBs, evidence based medicine, and sophisticated statistical analyses. I am fortunate to work with him as a colleague and continue to learn when he lectures. I have many of his original papers and share them with our fellows. Best.

Paul Segal
Assistant Professor of Medicine, Division of Nephrology,
Johns Hopkins, Clinical Nephrologist and Informatician

BTW…no nod to IS Edelman in your Sodium lecture?

In a follow up letter he elaborated on Edelman:

Getting back to Edelman, to me, the equation essentially describes everything you need to know about treatment by examining both the numerator and denominator. In addition, it reminds students that potassium is an important component of plasma sodium (as per T Berl and A Rastegar’s AJKD article 2010), and a component of EFWC.

Great stuff thanks.