UpToDate can be so entertaining, I mean deceptive

I am working on a review of membranous nephropathy and I found this quotation from UpToDate:

A random urine protein-to-creatinine ratio should NOT be used for initial risk stratification, since the relationship between the ratio and 24-hour protein excretion varies widely among patients (show figure 2).

This surprised me. I use the protein-to-creatinine ratio all the time and, though I have found some individuals where it is wildly inaccurate, I had been unaware of any data that showed that to be the case.

I eagerly clicked the link to the figure and this is what I found:

That looks highly accurate to me. Every data point clusters right along the line of identity. I pulled the abstract (alas, no full text from NEJM 1983) and found this conclusions from the authors:

In a study of 46 specimens we found an excellent correlation between the protein content of a 24-hour urine collection and the protein/creatinine ratio in a single urine sample.

I love UpToDate but this is really disappointing. Making a claim and referencing it with data which disproves the claim is disingenuous.

UpToDate, you need to do better.

How do you go from an EGD to acute kidney injury?

We had an interesting consult a few weeks ago.

The patient was an elderly gentleman who recently underwent an EGD for gastritis-like symptoms. A few days after the procedure he received a call from his gastroenterologist telling him that he had H. Pylori and needed to start an antibiotic. He was prescribed PrevPac for 10 days. He almost immediately began to feel worse. His wife ultimately stopped giving him the PrevPack after about four days of increasing weakness, lethergy and nausea. Despite stopping the new medicine the patient continued to deteriorate. He was admitted about 2 weeks after the EGD.

His creatinine had risen from a baseline of 1.2 mg/dL to 4.5 mg/dL. Our initial thought was that he was pre-renal. We prescribed 0.9% saline but the patient didn’t respond, and his creatine continued to rise.

One clinical pearl that I repeatedly teach fellows is not to under treat pre-renal azotemia. If you think the patient is volume depleted give enough fluid that the next day if the creatinine has not improved you will be convinced that the patient is no longer volume depleted. You want to fully rule-out volume depletion after the first day.

This patient didn’t respond to fluids so we reevaluated the history. PrevPac, what’s in that?

  • Lansoprazole
  • Amoxicillin
  • Clarithromycin
Clarithromycin is a potent inhibitor of CYP3A4 so it interacts with a lot of medications. Our patient was on simvastatin. Let’s check out what does Dr. Google has to say about that:
We check his CPK and its 8,000 almost a week after he stopped taking the Clarithro.

Rhabdo induced acute kidney injury due to a drug interaction.

Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Clarithromycin is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism.

Effects of Clarithromycin on the Pharmacokinetics of SimvastatinCompared with simvastatin alone, coadministration of clarythromycin and simvastatin significantly increased the peak concentration and the area under the curve for simvastatin by approximately 8-fold (p<0.0001). Levels of simvastatin acid were also significantly (about 14-fold) higher during clarythromycin treatment compared with simvastatin alone (p<0.0001).

If the figures on pharmacokinetics from that last article are to be believed then 500 mg of clarithromycin magnifies 80 mg of daily simvastatin to an equivalent daily dose of 640 to 1,120 mg.

Rhabdomyolysis induces acute kidney injury from myoglobin. Myoglobin can precipitate in the presence of acidic urine. The heme component of myoglobin can generate free-radicals which can damage lipid membranes. Patients develop vasoconstriction in response to rhabdomyolysis, both from the direct effect of the myoglobin on the renal vasculature and due to the movement of intravascular fluid into the damaged muscles. This gives a pre-renal picture on the fractional excretion of sodium.

Evaluating volume status can be tricky because patients will often have peripheral edema from the inflammation associated with the rhabdomyolysis. Additionally the BUN:Cr will often be low as the creatinine tends to rise quicker in rhabdomyolysis than in other forms of renal failure. This is usually explained by the release of intramuscular creatinine rather than just a failure to clear creatinine. The younger age and increased frequency of men suffering from rhabdomyolysis may also play a role in this observation.

The electrolyte abnormalities of rhabdomyolysis:

  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia (early)
  • Hypercalcemia (late)
  • Hyperuricemia
  • Anion gap metabolic acidosis

 The NEJM recently did a nice review of rhabdomyolysis which presents the recent inconclusive data on alkalinization (not proven to be helpful but the animal/disease models make it look like the right thing to do), mannitol and diuretics and use of high flux dialyzers.

The Annals of Internal Medicine recently published a review of Statin-Related Myopathy. Here is what they had to say about drug interactions:

Because simvastatin, lovastatin, and atorvastatin are primarily metabolized through the cytochrome P450 3A4 (CYP3A4) isoenzyme (43), inhibitors of CYP3A4 could theoretically increase serum statin levels and exposure to susceptible tissues. Drugs known to interact with statins include protease inhibitors, cyclosporine, amiodarone, and fibrates (44, 45). Protease inhibitors are potent CYP3A4 inhibitors and thus can increase up to 30 times the plasma concentrations of certain statins (45, 46). Consequently, both simvastatin and lovastatin should be avoided in pa- tients receiving protease inhibitors (42, 45, 47). Cyclosporine is a potent inhibitor of not only CYP3A4 but also several membrane transporters, and it increases the phar- macokinetic area under the curve of statins by 2- to 25- fold, with many reported cases of rhabdomyolysis (44). Statin dosages in patients receiving cyclosporine have therefore been limited to 5 mg/d for rosuvastatin, 10 mg/d for simvastatin and atorvastatin, and 20 mg/d for lovastatin (42, 47–49).

Pravastatin is not metabolized by the P450 system but is excreted renaly. Fluvastatin and rosuvastatin are metabolized by an alternative enzyme, CYP2C9.

Acid-Base Chapters (Chapters 10-16) from Fluids

Chapter 10: Introduction to Acid-Base

Chapter 11: Introduction to Metabolic Acidosis
Chapter 12: Non-Anion Gap
Chapter 13: Anion Gap Metabolic Acidosis
Chapter 14: Metabolic Alkalosis
Chapter 15: Respiratory Acidosis
Chapter 16: Respiratory Alkalosis

Why I love the Mac

To bring my readers the Fluids book I had to merge multiple PDFs into a single document. For example, the Hyponatremia chapter exists on my hard drive as 4 separate pagemaker files. These can be converted to four separate PDFs. To put them together is trivial in Mac OS X. No Acrobat Pro or other nonsence needed:

From the Apple website

And from with a little more context from Mac OS X Hints

Use Preview to open up the two PDFs you would like to merge. Choose View » Show Sidebar (or click the Sidebar button). Make sure both PDFs are visible on the screen at the same time. When the Sidebar pops out, you will see a graphical representation of the pages in your PDF document. Simply drag the page, or pages (use Comand to select multiple pages) from the Sidebar of one PDF to the Sidebar of another. You have now merged pages from two separate PDF documents.

So easy. So simple. So elegant.

The Fluid and Electrolyte Companion has been locked up

The Fluid, Electrolyte and Acid Base Companion was a book I co-wrote during my residency. We started the book in 1995 after graduating and finished it during the summer of 1999. The book came out in January 2000.
The book was a home brew project with no professional assistance. We researched the book, wrote the text in Adobe Pagemaker and did the illustrations in Adobe Illustrator. All the computer work was done on Apple computers. This was a time before OS X and we suffered through the dark days of System 7.5.5, the Vista of Apple operating systems.

When the book went to press the source files were primarily a mixture of Pagemaker 6.5 and Illustrator 8.0. Significantly, we never upgraded to Pagemaker 7.0.

After we finished, Adobe put Pagemaker out to pasture and replaced it with InDesign. Adobe never released a version of Pagemaker that ran natively in OS X and the tools they created for moving from Pagemaker to Indesign required the files to be Pagemaker 7 files. Our 6.5 files were an evolutionary dead-end. No way to get them to Indesign. Then, as my interests turned away from the book and toward the rest of my life I started snipping the threads that allowed me digital access to the Fluids files. In 2001 I transitioned from OS9 to OS X and had to use Classic to open up the book or use Pagemaker. In 2008 all of the Macintosh’s in my house (my laptop, desktop, and wife’s laptop) were finally upgraded to Intel processors which meant that they could no longer run Classic which locked me out of the book. Functionally it was no different than if my hard drive had crashed and I had lost all of my back-ups.
When I started this blog, one of the things I thought I would use it for would be as a tracking tool as I rewrote and modernized the original Fluids book. Well for the last 18 months I have been stuck on the very first step of this process: getting electronic access. I finally solved that problem by getting my hands on a vintage 12 inch PowerBook that was in one my parent’s closets.
Last week-end I found my old Pagemaker and Illustrator disks and installed them under classic. Then I looked deep in some old hard drive back-ups to find all of the fonts needed to render the files. Finally, after some deep Googling, I came across this work-around to create a PDF from Classic. So here is the first chapter of the Fluid, Electrolyte and Acid Base Companion:
I hope to follow this with an edited version of this chapter and then move on to the subsequent chapters and really provide a modern, comprehensive tutorial towards fluids and electrolytes aimed at medical students and residents.
David Pogue did a nice piece on this for Sunday Morning
In the future, I’m going to need to try this and see if it allows me to run my old programs on my current laptop.