Thursday, April 17, 2014

Monday, April 14, 2014

Passover is Here Again! Updated with a working link.

Newest version of my Passover Haggadot, now for iPad!

For the link to work you will first need to install iBooks.




Friday, April 4, 2014

#NephMadness, choices we made.

After next Tuesday, all that will be left
will be to send out the prizes.
NephMadness announces the finals today and the winner next Tuesday. As the field has contracted we have been feeling the pressure. People we respect have questioned our choices. Some have pointed to our final four, JNC8 and Acute PD in particular, and had some negative thoughts abut their importance.

I’m sorry they are disappointed with the final four. I personally am more concerned with the elite eight* than the final four, as the elite eight represents the champions of each region. The elite eight were:

  • Toxins: Aristolochic acid
  • Renal replacement therapy: Urgent PD
  • Hypertension: JNC8
  • Regeneration: pericytes
  • Acute kidney injury: Balanced fluids
  • Electrolytes: Bicarb in CKD

  • Stones: Acute Medical Care
  • Biologics: belatacept
* Any one else feel that the Final Four and the Sweet Sixteen, make it feel that eight should be an alliteration? But the sad reality is, elite and eight are not alliterative. I prefer Great Eight.

Looking over this list I am comfortable and enthusiastic about each choice (except for pericytes which I still don’t understand but Matt and I didn’t want a dream, bioartifical kidney, to win. When they can keep that Frankenstein Kidney alive for more than a few days without clotting we'll reconsider).

JNC 8

JNC8 is the most important issue in hypertension because it is leading a massive sea change in the blood pressure standards of hypertension around the world. JNC8 is largely in agreement with all of the national guidelines that have been published world wide.

JNC 8 vs ASH/ISH
For one, the start-treatment threshold of >150/90 mm Hg applies to patients 80 years or older in the ASH/ISH guidelines, as opposed to 60 years or older in JNC 8.
AHA/ACC/CDC joins JN8 in not calling for stricter, lower, blood pressure targets in the presence of CKD, diabetes, or proteinuria.

JNC 8 versus KDIGO

Everywhere hypertension experts have been reconsidering previous aggressive blood pressure targets. In the end, the blood pressure targets of JN8 are not based on firm data that fit every clinical scenario and we may end up revising them in the face of future data but these guidelines will determine the future of stroke, coronary disease, heart failure and kidney failure for millions of people being treated for hypertension.

Additionally, JNC8 and the ACC/AHA cholesterol guidelines together usher in a new era where observational data is no longer considered acceptable data to base guidelines. This resulted in a relaxation in both cholesterol and blood pressure targets. This is a sea change in how guidelines are developed. This is important. JNC8 also grades the evidence. E level evidence, i.e. expert opinion, on such a fundamental question as systolic blood pressure target, should be humiliating to the hypertension community. I believe that letter grade will stimulate the community to find the answers definitively. I salute the guideline writers for having the courage to admit that the emperor wears no clothes.

Urgent PD

Urgent PD triumphed in the renal replacement therapy region. We chose this because it is the first innovation in peritoneal dialysis in the last 20 years that seems capable of moving the needle and reversing the trend of dwindling number of patients on home therapy.

Two years ago there were one or two programs in the country, today there are over 100 urgen PD programs. PD, according USRDS is $20,000 a year cheaper to administer than HD and considering that 115,000 people initiate dialysis every year the savings quickly exceed my ability to track the zeros (9, I think). No one knows if PD is better than HD, and it probably is roughly equivalent, but it is definitely cheaper. Urgent PD is an innovation that shows promise in increasing the numbers of people in PD. After starting an urgent PD program we doubled our PD population after years of decline. When I mentioned that story to others who had urgent start PD programs they nodded their head and say the same was happening at their centers.



NephMadness Decisions

We did not make our decisions without thought and it is inevitable that others will have different values when it comes to these ambiguous and irrational comparisons. I am comfortable with the decisions that we made and do not feel we are limping to the finish line.

Tuesday, April 1, 2014

#Nephmadness Explanations: Serum Anion Gap

The fall of the serum anion gap.
The serum anion gap was an entry on the electrolyte region of NephMadness. It won it's opening round over urine anion gap and advanced to the Sweet 16 by beating hypertonic saline but failed to win the electrolyte region when it fell to Bicarbonate in CKD.



CJASN did a recent review of the anion gap and they were frank with its limitations:


Some interesting notes about the anion gap: though the serum potassium was included in the original derivation of the calculation, none of the major U.S. textbooks include it. The upper limit of normal anion gap from the 8 sources included in the paper is much higher than I teach. I use 12 and after the ASN Board Review Class, I remember feeling that was too high.


The article then discusses the fact that ion selective electrodes are more sensitive for chloride so they detect higher chloride concentrations so that average and pathologic anion gaps are lower.

The article discusses the importance of albumin in the normal anion gap. As albumin falls, either the limit for a pathologically elevated anion gap needs to fall or the calculated anion gap needs to be adjusted upwards. The article recommends the latter. The anion gap should rise 2.5 for ever 1 g/dL the albumin falls below normal (presumably 4 g/dL). The authors recommend that albumin adjustments be incorporated into laboratory reporting so clinicians do not need to worry about this.
The meat of the article is contained in table 3 where the authors review 5 studies that looked at the sensitivity of an increased anion gap for lactic acidosis. It's not a pretty picture.


The anion gap is meant to be a screening test, if it is positive the specific cause of the increased anion gap can be investigated with specific assays. Screening tests are supposed to be sensitive so that if they are negative one can rule out that potential diagnosis. Here we see that the anion gap is wearing no clothes. Sensitivity can be as bad as 43%, but typically runs around 60-70%.

In Adams et. al's (PDF) analysis of emergency department patients, 50% of patents with a lactate level between 5 and 9.9 had an anion gap below 12!


The authors theorize that the anion gap fails due to the broad range of normal in the anion gap. The normal anion gap can range from 3 to 12, so suppose a patient is sitting at the low range of normal say 3 or 4, they could absorb an lactate level up to 8 or 9 mmol/L while still maintaining a normal anion gap. See the illustrations with Gamblegrams below:

Both James and Jean Luc start with normal anion gaps, though James is at the upper limit and Jean Luc is at the lower limit of normal.

Both patients develop equivalent and significant lactic acidosis but only James develops an anion gap
The article then describes some unusual behaviors of the anion gap. The first is that the anion gap can rise more than the bicarbonate falls. A basic tenet of the anion gap is that the ratio of the change of bicarb and the anion gap is 1:1, this is the theory that the delta gap equation rests on. In lactic acidosis apparently the the anion gap can rise 1.8 for every fall in the bicarbonate of one. The net result of this is patients can have significant lactic acidosis in the presence of a normal serum bicarbonate.

Additionally, patients with identified organic acidosis, the identified acid typically does not explain the entire gap. 

The authors discuss some data on using personalized normal anion gap targets from previous labs. This would help the sensitivity of the test in patients who run low normal anion gaps and have a hard time cross the threshold for an increased anion gap (see Jean Luc above). However, the authors point to a study (Lipnick et al. 2013) which used this technique and still missed approximately 30% of lactic acidosis cases.

This is a good article but it does not address issues such as the the anion gap's usefulness in the diagnosis of the toxic alcohols and its use in the management of DKA.

Sunday, March 23, 2014

Friday, March 21, 2014

NRMP Crack

I just heard about this yesterday and loved the irony. The NRMP which toys with the emotions of med students everywhere by holding back match results until that wonderfully cinematic moment on Match Day, accidently leaked the match results. Shoddy programming.

Here is the thread from redddit.

Here is a blog post about the slip up:
As you can imagine, this created QUITE a stir, as medical students around the country have been waiting, stressed out of their minds, about where they will be assigned to go to residency for the next 4-7 years. A flurry of online activity ensued, as medical students already pushed to the brink took to their browser’s source codes to figure out their futures. Apparently the programmers “preloaded” the match homepage source code with the information of where people match, so that once the magic time hits on Friday, they can easily change everyone’s NRMP homepages to reveal the new result. What they didn’t realize? That there are medical students out there who are combing every detail of the site to figure out anything they can ahead of time. Several took it upon themselves to poll all of their friends to assess the accuracy of this method.
So today's match day will have a little less drama, for every fourth year who was not obsessing over the match results.

Happy Match Day. Good luck and "...may the odds be ever in your favor."

NephMadness. The story behind the brackets.

Last year, NephMadness came together in about 4 weeks from concept to Selection Sunday. Because of the short time available, and the fact that we had no idea what we were doing, somethings worked and others flailed. Since we are in the middle of a bracket fever epidemic, let's take a critical look at last year's brackets with a focus on the changes we made in 2014.

2013 brackets                    2014 brackets

The most important thing we got right, was dividing the field into 8 regions of 8 teams and assigning unique themes to each of these regions. In 2013 the 8 themes were:
  1. Big organized programs like Medicare ESRD benefit and USRDS
  2. Research techniques like randomized controlled trials, propensity scoring and epigenetics
  3. Randomized clinical trial like TREAT, IDEAL and ALLHAT
  4. Molecules and genes, think FGF23, Cystatin C, APOL1
  5. Drugs like captopril, cyclosporin and tolvaptan
  6. Educational resources like UpToDate, Renal Fellow Network and Wikipedia (yeah, we went there)
  7. Equations we use Winter's formula, MDRD, FENa
  8. Renal procedures like kidney biopsy, scribner shunt and plasmapheresis.
This provided a degree of rationality to an inherently irrational game. Where we fell down is when we didn't adhere to the themes. Look at the molecules and genes region, somehow MPGN reclassification and HIVAN slipped in. 
Likewise in the procedures section we had an eclectic group that included completely disjointed procedures such as transplant, citrate anticoagulation and the Scribner shunt.
The other primary weakness of the 2013 field was that there were a few overwhelming stands outs. Just glancing at the tournament a few Goliaths stood out that you just knew were going to end up in the final four. Here was our final four from last year:
  • Captopril (1) 
  • Medicare ESRD benefit (1)
  • HEMO trial (1)
  • Transplant (2)
Three number one seeds and a number two seed. Looking over this year's brackets, I don't see obvious candidates for the final four.

When we started thinking about assembling the field for 2014, we decided to get outside help. The plan was to work with experts in various corners of nephrology to unearth some gems that the core editors of NephMadness would never have considered.

An example of this working to perfection was in Kidney Stones.

David Goldfarb, immediately grokked the game and over the course of an hour long phone call filled his brackets with great pairings that hit on stone issues relevant to nephrologists. He selected teams that represented diagnosis, treatment, the future and the past. He built a bracket that we, literally, could not have done without him.

It has been great, getting a chance to correct the mistakes of version of 1.0 to build something of quality. I have to say that the most rewarding part of NephMadness was putting together the selection committee and talking with them about their area of expertise. Just letting an expert who has spent her whole life studying one corner of nephrology expound on what is so important and exciting about that field was super enjoyable. (Unless, they didn't get NephMadness, and in that case it was more like a root canal) 

The NCAA tournament has started but you can still join NephMadness. Get in the game before Wednesday, March 26th.

Tuesday, March 18, 2014

Dialysis for toxic alcohols, new empiric data

Why I love twitter.




Immediate download.

See if you can get a few more authors next time.
Interesting introduction in the article about the disparity betweeen cases and resources for treating methanol. Most resources  are available in the developed world (dialysis, fomepizole) but most cases occur in the developing world. Also interesting note was that some Islamic Countries have social bans on the medicinal use of alcohol. That could make treatment pretty dicey.

They prospectively observed 24 cases of methanol ingestion out of 121 cases in a mass methanol poisoning in the Czech Republic. Looks like it was due to contamination of spirits with industrial methanol. Apparently this is a relatively common problem.

41 deaths. All patients in the observation cohort were treated with ethanol (17 patients) or fomepizole (4) or both (3) to prevent conversion of methanol to the downstream toxic metabolite, formic acid.
15 years old and this page still stands-up. Some stuff never changes.
Page 358 of the Fluids Book.
.
The authors present clearance data on 11 patients treated with conventional dialysis and 13 treated with continuous dialysis.

The half life of methanol with conventional dialysis was 3.7 hours and 8.1 hours with continuous dialysis. Not suprisingly all of the componants associated with more efficient dialysis were associated with with faster clearance of methanol: increased dialyzer surface area, increased blood flow and increased dialysate flow. Those half-lifes are remarkably shorter than the half life of methanol in the body using renal and pulmonary clearance.

On the other hand folate supplementation, the pre-dialysis methanol level and the nature of the antidote (ethanol versus fomepazole) made no difference.

The shorter half-life with intermittent conventional dialysis did not transplant into better patient survival.

They turned their math into specific treatment guidelines.

Some interesting tidbits. You know that graft that shows that the osmolar gap falls as the anion gap rises?
Canadian Family Physician
That wasn't the case so much here, they found simultaneous high anion and osmolar gaps.




Saturday, March 15, 2014

Fun with Twitter: Add a word, make a nephrology band

My post for World Kidney Day

Things a re a bit frantic with the start of NephMadness just over 24 hours away.
I posted on World Kidney Day at Medium but I failed to link to on PBFuids. Sorry.

My very optimistic post for WKD

I'm going to be doing more and more of my posts on Medium, it is so much better than WordPress or Blogger for composing and displaying my words.

Monday, March 10, 2014

Follow-up from the Herbal Supplements Lecture

I received a delightful e-mail from Arthur Grollman, world expert on Aroistocholic Acid.

Dear Dr Topf, 
I congratulate you on assembling and sharing this very nice presentation and, wisely, connecting it to the problems associated with politicians, supplements and DSHEA.  We have written some articles about this connection as well. 
I give a similar lecture to medical students and another focussed on BEN [ed: Balkan Endemic nephropathy] and aristolochic acid nephropathy for Medical and Nephrology Grand Rounds as most of the research being done on that subject since 2005 has been done in our lab. 
A few comments on the historical sequence:
  • JP Cosyns is the Belgian pathologist who first recognized the similarity to BEN but did not follow up the lead
  • Tjassa Hranjec, a medical student at Stony Brook, doing a summer fellowship conducted the personal  interview with the farmer you attributed to me. She
  • was doing a pilot epi study, under my direction, to determine how we should investigate BEN
  • The first experimental evidence for the role of AA in AAN and UTUC appears  in our 2007 PNAS paper
  • The Serbs and the Bosnians still believed that their BEN was a different disease, so we expanded the number of cases and included those countries in the cover story paper in KI in 2012.  DeBroe wrote a commentary to accompany our paper which convinced any remaining skeptics of the validity of our guiding hypothesis: AAN = CHN = BEN
  • Wondering how Aristolochia herbs could have been used throughout the world for 2000 years without one mention of toxicity or urothelial cancer, we conducted the study in Taiwan, where one in three people have ingested the Aristolochia herb according to the prescription database.  The results are in our 2012 PNAS paper.
We continue to work on this fascinating nephrotoxin/carcinogen for which, as you see has a "signature mutation" and is likely to affect tens of millions of people in China.  And the road to its recognition started exactly as you said in your talk, with the two
Belgian women in Vanderwegen's clinic. He told me that his own clue came when he walked from his office to the clinic and found a number of women talking to each other which was unusual. He asked them how they knew each other which led immediately to the identification of the spa. 
With best regards 
Arthur P. Grollman M.D.
Distinguished Professor of Pharmacological Sciences
Evelyn Glick Professor of Experimental Medicine
Director: Laboratory of Chemical Biology
Health Sciences Center BST-8-160
Stony Brook University

The e-mail included some great images. Two covers from nephrology journals:



Gorgeous picture of DNA Adducts
Grollman won the 2011 Environmental Mutagen Society Award. As part of that award he wrote an invited review on aristocholic acid nephropathy. I'm looking forward to reading it. It has some great drawings. Take a look at the figure below the abstract. Wow.


Friday, March 7, 2014

NephMadness is returning!

The NCAA March Madness tournament with a nephrology twist. Get all the details at NephMadness.com
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