ACEi, ARBs and Aldo Antagonists and the risk of Contrast Nephropathy

This is a question that comes up during almost every consult in patients with CKD about to receive contrast exposure. Should we stop ACEi and ARBs prior to exposure?

The data is confusing as summarized in the introduction to this latest analysis:

...Some studies have demonstrated that chronic medication with angiotensin-converting enzyme inhibitors (ACE-I) or AT-1 blockers was a risk factor for CIN [19,20], whereas other studies [21,22] found a protective effect in patients with CKD when exposed to CM.

If that doesn't meet the definition of equipoise, I don't know what does.

There still isn't any prospective data but a recent reanalysis of a large (negative) trial on the use of hemodialysis to prevent contrast nephropathy attempts to answer the question.

When the baseline characteristics are separated by the presence of contrast nephropathy it reads like a rogues gallery of risk factors of contrast:

All of the following were significantly more frequent (or more extreme, i.e. greater age, higher Cr, more contrast, lower eGFR) in patients who developed contrast induced nephropathy:

• Age
• Diabetes
• Insulin dependent
• Creatinine
• eGFR
• Hemoglobin (that's new)
• RAAS blockade (ACEi, ARB, and aldo antagonist)
• Loop diuretic
• Contrast dose

The multivariate analysis showed RAAS blockade and hemoglobin to be independent predictors of contrast induced nephropathy:

The data is sure suggestive of an effect but given that both CKD and CHF are risk factors for contrast nephropathy and RAAS blockade is a first line therapy for both diseases I fear we could be looking at a classic bias by indication.

This is a question that is begging for an interventional trial. I'd let my patients be randomized to d/c ACEi/ARB versus no discontinuation. It sure would be better than another damn study on loop diuretics, mannitol and IV fluids 2009 (Hey AJKD! 1994 is on the phone and they say they'd like their study back).

Plavix drug interaction

I know I'm a little late on this, but here is a sign we are using in our offices to alert patients to the problem with clopidogrel and omeprazole. Thought it might be useful for others.

Plavix Warning

Good article on gout

Nice perspective on dietary causes of gout by Gary Taubes.

Gout the missing chapter...

Contrast and residual renal function

In a previous entry I reviewed the iPhone app PubMedOnTap. I used this application to find articles regarding the question of whether iodinated radiocontrast media harms residual renal function for patients on dialysis. I came up with two "hits."

• The first is an article by Paul Palevski's team at Penn.
• The second is by Janousek et al. from the Czech republic. 

The Palevski study is a retrospective analysis of PD patients with residual renal function who underwent coronary angiograms. They compared residual renal function after the angiogram to previous residual renal function. They also looked at mortality, change of modality and peritonitis. They created a control group composed of patients matched for time of initiation of PD, age, and diabetic status.

29 patients met the enrollment criteria. Residual renal function was assessed an average of 14.7 weeks following the procedure. 1 patient became permanently anuric following the angiogram.

The average loss of renal function for the cases was 0.09 ml/min/month versus 0.07 ml/min/month for the controls (p=0.53). Average decline in residual renal function for PD patients is said to be 0.1 mL/min/month.

5 patients had no residual renal function measured after the angiogram and a medical record review could not document why this happened. They were censored from the final analysis.

The Janousek study is a more rigorous design, as it is controlled. They did a matched cohort study of hemodialysis patients who underwent a endovascular procedures and matched them to similar patients who did not receive contrast.

All the participants had to have at least 500 mL of urine production per day.

The contrast patients received an average of 99 mL of iodixanol (isoosmolar contrast, Visipaque) with a range of 60-180 mL.

The authors specifically state that

Our aim was not to evaluate the immediate effect of contrast medium on residual renal function during the several days after application. Rather, we wanted to evaluate its long-term clinical effect. This is why we compared the volume of daily diuresis and RREC 3 months before and 3 months after ICA administration.

They found no difference in the rate of loss of residual renal function whether they measured it by urine volume (p=0.855) or creatinine clearance (p=0.573).

From the change in urine volume (the top chart), the value of a placebo group becomes clear. The contrast group does lose urine volume, but they lose it at roughly the same rate as the control group.

One of my concerns about the study is that since it was retrospective they purposefully restricted their analysis to patients who survived for the entire 6 month follow up period. From the Materials and Methods section:

Only clinically stable patients with no serious concomitant disease and who survived for a 6- month follow-up period with an unchanged dialysis strategy were evaluated.

So if contrast caused pre-mature death in dialysis patients, subjects having that outcome would not have been studied.

In the discussion the authors mention three other articles on the same subject:


They found two in NDT in addition to the pavlesky article. None showed a deleterious long term effect of contrast.

• The first was a prospective trial by Dittrich el at. of 10 peritoneal dialysis patients with 8 patients as controls. They found a temporary drop in residual renal function that was erased after 30 days.

• The second was a prospective cohort trial by Morrane et al. of 72 peritoneal dialysis patients, half of which were exposed to contrast. After two weeks there was no difference between the two groups or from baseline figures in regards to CrCl, urine volume or residual renal function.

How to make a cool clinic diagnosis

I had a great case yesterday in clinic.

The patient was a 55 year old woman with HIV and a chief complaint of gradually climbing creatinine. Among her medications were Truvada and Norvir.

Truvada is one of three brand name drugs that contains tenofovir:

1. Viread: tenofovir
2. Truvada: emtricitabine-tenofovir
3. Atripla: efavirenz-emtricitabine-tenofovir

Tenofovir rarely causes renal failure through proximal tubule toxicity. One of its hallmarks is a Fanconi syndrome, though the renal failure can occur without Fanconi's. Fanconi' syndrome is generalized dysfunction of the proximal tubule, so metabolites normally reabsorbed in the proximal tubule are wasted in the urine. Patients have amino aciduria, bicarbonaturia (RTA type II), inappropriate phosphaturia and glucosuria. Because of the increased phosphaturia, hypophosphatemia is a surprisingly sensitive indicator of tenofovir toxicity (20/20 cases).

This patient's creatinine rose from 1.4 in March of '09 to 1.7 in November. The primary care doctor that handles this patient's HIV had checked an ultrasound (9 and 10 cm kidneys), and albuminuria (400 mcg/min).

Here are the results of his U/A we did in the clinic:

I focused on the glucosuria and concluded that if her blood sugars are normal then she must have proximal tubular dysfunction and likely tenofovir toxicity.

Her blood sugar was 87. The Tm for glucose is roughly 200, so a serum glucose of 87 should not cause any glucosuria.

The Truvada was stopped. The patient is also on ritonovir (Norvir). Ritonovir is found in 72% of patients with tonofovir induced Fanconi's syndrome, so it maybe an important co-factor in the development of this condition. We did not stop the Norvir, should we?

 I will follow up with the patient in the month. Hopefully she will do well.

Here is a talk I gave on HIV and the Kidney:

HIV and the Kidney 2009

View more presentations from Joel Topf.

Great web service for making booklets

My favorite way to lecture is to pass out a personally written chapter on the subject and then collectively read the hand-out. I call this lecturing "Seder-style" named after the ritualistic dinner of the Jewish holiday Passover.

The booklets have four pages on each sheet of paper but you need a computer program to reorder the sheets so the booklets come out right. I used to have a print service that did this for me but it stopped working when I upgraded to Snow Leopard. I found this web service BookletCreator which does a great job with this.


Here are the original PDFs I uploaded:

• Sodium and Water
• Potassium

Here are the bookletized PDF the website created:

• Sodium and Water (booklet)
• Potassium (booklet)

Perfect.

UPDATE: No longer free.

PubMed on Tap for the iPhone: the NLM in your pocket

Last week at the end of a morning conferance there was an impromptu discussion of the problem of residents ordering IV contrast for patients with acute kidney injury. The residents see a patient on dialysis and feel that its open season for contrast.

As part of the discussion one of the attendings mentioned this is also a problem with his PD patients with residual renal function and the residents need to know that contrast should be avoided in these patients to preserve residual renal function. I mentioned that actually the data doesn't support the common sense notion that contrast accelerates the loss of residual renal function. Immediately all eyes were on me and the consensus was that no one else had seen that data and that I was way off the reservation. Pretty uncomfortable place to be.

I had buttoned holed Paul Palevsky at the 2006 ASN Renal Week after a talk on contrast nephropathy and in that hallway conversation he had mentioned that he had just finished research on this vary question. he only reason I remember it was that the results were so counter intuitive. Contrast has no measurable affect on residual renal function. I had actually never seen the article but now I had put up or shut up.

After the conference I had to run to an outside hospital but I stopped at a Tim Hortons (the best thing to come out of Canada since Douglas Coupland) and fired up PubMed on Tap (PMT).

PMT is an app dedicated to adapting the PubMed database to the constraints of a mobile platform. I used an app by the same name on my old Treo. Adding Palevsky as author, and then contrast and residual renal function as text words.

Bingo! One article:

You can pull up the abstract:

The PDF:

 :

and the PubMed listing:

I then did a less specific search by dropping the author name and found a higher quality study:

I was able to send the references to my colleagues right from the application. Sweet.

Great resource on potassium

kind of an "everything you wanted to know about potassium but were afraid to ask."


I especially love the two Nobel prizes in the top corner. Pauling is one of only four people to win two. In an alternate universe Linus got a couple of breaks to beat Watson and Crick to the structure of DNA. In that universe he has three Nobels and walks around like Michael Phelps.

What are the top nephrology stories of the last decade?

As we come to the end of the naughts, we naturally reflect back and think about how far we have come from in the last ten years. Here is my quick list:

1. MYH9 gene for ESRD
2. The failure of the normalization of hemoglobin and the wholesale reevaluation of ESAs
3. The rise of aldosterone and its importance in hypertension and renal disease
4. the failure of dialysis dose to improve out come in both chronic (HEMO) and acute dialysis (ATN).
5. FGF-23, hey a whole new hormone and a major advancement in renal physiology
6. Re-emergence of home dialysis
7. Problems with the definition of CKD and the problems with eGFR
8. discovering the antigen in idiopathic membranous nephropathy

I want to do a longer article about this but I'm sure I'm missing some stuff. I don't have a transplant subject, seems like vitamin D belongs up there, what about the phos binder wars? Bundling? What about MMF in lupus nephritis and every other GN?

week-end call and a pair of crazy numbers: Glucose and Calcium

Glucose

I saw the highest glucose I can remember in a patient without ESRD. I have seen the glucose go over 2,700 in a patient with the misfurtune to have both DKA and anuric ESRD. Without the osmotic diuresis to lower the glucose the glucose can shoot the moon. This patient had HyperOsmolar Non-Ketotic Coma (or HONK as my fellow calls it, love that) and baseline Cr of 0.83 and a peak glucose of 1,600 mg/dL.

I love the twin graphs showing the falling glucose and the simultaneous resolution of the pseudohyponatremia. The patient had enough pre-existing osmotic diuresis to cause hypernatremia which was masked by the hyperglycemia. As the glucose comes down the sodium goes up from 136 to 162.

Calcium
The other crazy number was the most severe hypercalcemia I have ever seen. The calcium was 18 mg/dL with an albumin of 3.7 g/dL. The patient is a kidney transplant recipient who was recently seen in the outpatient clinic with hypocalcemia. His calcium was 6.5 and his calcitriol was increased from 0.5 mcg to 1 mcg twice daily. He was also continued on his calcium carbonate.

Admission labs:

The other pertinent calcium labs:

• PTH: 3.2 pg/mL
• Vit D 1,25 dihydroxy: 36 pg/mL
• SPEP/UPEP: unremarkable
• PTHrp: pending

I think this is milk-alkali syndrome from the calcium carbonate exacerbated by the calcitriol. One supporting string of evidence supporting this is the fact that his calcium came down and has not reoccurred. If it was hypercalcemia of malignancy I would have expected his calcium to be resistant to conservative therapy.  

Cast Nephropathy and plasmapheresis

Does removal of the light chains with plasmapharesis reduce the severity of cast nephropathy? We know that renal failure is a terrible prognostic factor in multiple myeloma so fixing acute renal failure is important.

Renal failure comes in many different flavors with myeloma:

• Light chain deposition disease
• Heavy chain deposition disease that I have never seen but Steve Rankin had a case as a fellow.
• Amylloidosis
• Hypercalcemia
• Cast nephropathy

Only the last is amenable to plasmapheresis. Whether it works has been the subject of three prospective randomized studies:

1. Zucchelli 1988
2. Johnson 1990
3. Clark  2005 (PDF)

UPDATE

Though not randomized this recent article from KI should be of interest (Thanks Kyste):

Leung et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int (2008) vol. 73 (11) pp. 1282-8.

Highest urine urea ever

Just saw a urine urea of 1,019 mg/dL. I can't remember ever seeing one over 1,000 before. The FE Urea was 55% in a urosepsis induced AKI.

Fellow talk on sodium

I was scheduled to give a talk on disorders of sodium and water to the fellows yesterday. We have a particularly clever cohort of fellows this year and I really couldn't give them a warmed over version of my resident and student sodium lecture so I put together this talk which looks five different issues with hyponatremia and some data regarding them:

1. mannitol induced pseudohyponatremia
2. TURP syndrome
3. uremia and propensity for myelinolysis
4. exercise induced hyponatemia
5. differentiation of salt delpetion from SIADH with FENa, FEUrea and FE Uric acid with a couple of slides on treating SIADH with saline

Remember, downloading the native Keynote file will give you animations and a better  looking experience.

Hyponatremia

View more presentations from Joel Topf.

Engage with Grace Blog Rally

Last Thanksgiving weekend, many bloggers participated in the first documented “blog rally” to promote Engage With Grace – a movement aimed at having all of us understand and communicate our end-of-life wishes.

It was a great success, with over 100 bloggers in the healthcare space and beyond participating and spreading the word. Plus, it was timed to coincide with a weekend when most of us are with the very people with whom we should be having these tough conversations – our closest friends and family.

The original mission – to get more and more people talking about their end of life wishes – hasn’t changed. But it’s been quite a year – so we thought this holiday, we’d try something different.

A bit of levity.

At the heart of Engage With Grace are five questions designed to get the conversation started. We’ve included them at the end of this post. They’re not easy questions, but they are important.

To help ease us into these tough questions, and in the spirit of the season, we thought we’d start with five parallel questions that ARE pretty easy to answer:





Silly? Maybe. But it underscores how having a template like this – just five questions in plain, simple language – can deflate some of the complexity, formality and even misnomers that have sometimes surrounded the end-of-life discussion.

So with that, we’ve included the five questions from Engage With Grace below. Think about them, document them, share them.

Over the past year there’s been a lot of discussion around end of life. And we’ve been fortunate to hear a lot of the more uplifting stories, as folks have used these five questions to initiate the conversation.

One man shared how surprised he was to learn that his wife’s preferences were not what he expected. Befitting this holiday, The One Slide now stands sentry on their fridge.

Wishing you and yours a holiday that’s fulfilling in all the right ways.



To learn more please go to www.engagewithgrace.org. This post was written by Alexandra Drane and the Engage With Grace team. If you want to reproduce this post on your blog (or anywhere) you can download a ready-made html version here

I was taught that to live a long healthy life avoid alcohol and take your vitamins

Turns out that seemingly sound advice will kill'ya.

Headlines from this week:

Any drinking lowered the risk of heart disease but the more patients drank the greater the protection. And the amount they drank was pretty staggering:

• light drinking, about a glass of wine or 1.5-beers per day, reduced risk by 35%
• moderate drinking, 2 glasses of wine or 2-3 beers reduced the risk 51%
• Moderate and heavy drinking, 5+ glasses of wine or 7+ beers, resulted in 54 and 50% risk reduction.

The health benefits of alcohol were touched upon in ths prior post.

Not only did the patients randomized to folic acid + B12 have a higher rate of developing cancer, they had a higher cancer mortality. Most of the cancer mortality came from excess lung cancer in the folic acid + B12 group. This was despite the fact that there were more smokers in the placebo group (38% vs 40% p=0.01). (JAMA) 

The fall of folic acid was touched on in this prior post.

So parents, remind your kids to drink their beer and forget their vitamins.

Today we did the recent NEJM CRT dosing article in journal club

The article is here.

Three of our attendings and fellows raved about Dr. Tolwani's AKI in the ICU lecture from Renal Week.

Here is the slide deck.

Nephrotic syndrome + blood clots = membranous nephropathy

I have a patient with nephrotic syndrome, renal vein thrombosis and two pulmonary embolisms in the last year. I told him that the nephrotic syndrome was likely due to membranous nephropathy and that all of his various blood clots are due to the kidney disease. The biopsy came back today and it is indeed membranous nephropathy.

Membranous nephropathy is a common finding when patients are biopsied for nephrotic syndrome. Fortunately, it is a relatively benign disease with a significant number of spontaneous remissions. (Schieppati, NEJM 1993)

Adequate renal function was defined as "no ESRD"

Since there are so many spontaneous remissions and the therapy has significant side-effects we risk stratify patients in order to spare low-risk patients from treatment.

Higher risk

• older age (over 60) (Medline)
• male sex
• nephrotic range proteinuria
• greater than 8-10 g/day for more than 6 months (PDF)
• increased serum creatinine (Cr over 1.5) (Medline)

Though the instinct after getting a kidney biopsy is to start therapy immediately, in patients with a normal creatinine, waiting for 6 months and monitoring the creatinine and proteinuria does not alter the patients response to treatment. (Medline)

The biopsy findings have long been held of major importance on predicting prognosis but an analysis of 389 biopsies questioned whether histology provided information that independently predicted prognosis. (Medline)

Two urinary findings are gaining acceptance at being able to better predict the clinical course of disease. Beta-2 microglobulin excretion greater than 0.5 mcg/min and IgG excretion over 250 mg per day (others use the more sesitive value of 125 mg/24 hours) have both been associated with increased risk of renal progression. (Medline)

Treatment

Treatment recomendations are based on the probability of progression.

Low Risk
For patients with a low risk of progressing the recommendation is to stay and pray.

• Monitor the creatinine
• Institute non-specific antiproteinuric therapy (ACEi, ARB, aldosterone antagonists)
• Control the lipids
• Tight blood pressure control

Moderate risk

These patient should be initiaed on the Ponticelli or modified Ponticelli protocol. This calls for three consecutive two-month cycles of cytotoxic therapy.

1. Day 1-3: 1 gram of methylprednisolone. This is usually done as an inpatient.
2. Day 4-30: Oral prednisone, 0.5 mg/kg daily
3. Day 31-60: Oral cyclophosphamide 2 mg/kg (chlorambucil in the original Ponticelli)

High risk

Less data is available. Modified Ponticelli maybe appropriate but others recommend cyclosporin.

For patients with resistant disease there is no consensus on what is best and a list of what's been tried looks like a line up of the usual suspects, nephrology edition.

• Mycophenylate mofitil (Medline)
• Cyclosporin (Medline)
• Pentoxifylline (Lancet)
• Rituximab (Medline)
• Tacrolimus (Medline)

CJASN published an excellent review of membranous nephropathy (Medline).

Correcting secondary hyperparathyroidism with vitamin D

K/DOQI recommends spending 3-6 months correcting 25-OH vitamin D deficiency prior to graduating to active vitamin D to control secondary hyperparathyroidism in CKD patients. I have been aggressively treating vitamin D deficiency in my CKD clinic for years and have found a pretty modest affect on PTH. Generally you get 20-30% reduction in PTH by correcting 25-OH D but occasionally you get a real responder.

I just saw a patient with modest stage 3 CKD. When I first saw her she had a 25-OH D of 7 and a PTH of 288. I started her on 50,000 units of ergocalciferol a week. It took 12 months but we finally corrected her vitamin D deficiency and her secondary hyperparathyroidism just melted away.

Ezetimibe: The hits just keep on coming

The results of the ARBITER 6-HALTS study were published by the NEJM yesterday and they are not good. Great commentary over at KevinMD.

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 Simvastatin. Compared 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.

The Fluid, Electrolyte and Acid-Base Companion for Free

I have uploaded the entire Fluids book to Sribd. You can find all of the chapters in four posts:

1. Introduction and background
2. Sodium
3. Acid-Base
4. Potassium

Alternatively you can download the entire book (591 pages!) as a single PDF (28 mb).

Enjoy.

Potassium Chapters (Chapters 17-19)

17. Introduction to Potassium

17 Introduction to Potassium

18. Hypokalemia

18 Hypokalemia

19. Hyperkalemia

19 Hyperkalemia

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

Chapter 10: Introduction to Acid-Base

10 Introduction to Acid-Base

Chapter 11: Introduction to Metabolic Acidosis

11 Introduction to Metabolic Acidosis

Chapter 12: Non-Anion Gap

12 Non-Anion Gap

Chapter 13: Anion Gap Metabolic Acidosis

13 Anion Gap Metabolic Acidosis

Chapter 14: Metabolic Alkalosis

14 Metabolic Alkalosis

Chapter 15: Respiratory Acidosis

15 Respiratory Acidosis

Chapter 16: Respiratory Alkalosis

16 Respiratory Alkalosis

Dysnatremia chapters (chapters 6-9) of Fluids

Chapters 6 and 7: Hyponatremia

06 and 07 Hyponatremia

Chapter 8: Hypernatremia

08 Hypernatremia

Chapter 9: Polyuria/Polydipsia

09 Polydipsia Polyuria

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 first five chapters of the Fluids book

Chapter 1: Moles and Water

01 Moles Water

Chapter 2: Water, Where are You?

02 Water Where Are You

Chapter 3: Starling's Law

03 Starling's Law

Chapter 4: Volume Regulation

04 Volume Regulation

Chapter 5: Osmoregulation

05 Osmoregulation

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:

01 Moles Water

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.

The things patients bring in

My favorite patient encounters almost always involve the patient bringing in something they found in a newspaper or magazine. The best ones are fully annotated with the patients thoughts and comments. Typical subjects are: alternative medicine, vitamins, noni juice (don't get me started), new tests or scare mongering articles about drugs I have prescribed.

The other day one of my patients brought in a list of the 50 most prescribed medications according to the AARP. Jackpot.

I have transcribed the data into excel so I could abstract some of the data. The raw excel file is here.

I have three charts from the excel file that are interesting, the first is just a graph of the number of prescriptions with the retail cost overlaid. Can you spot the brand name drugs:

I then simplified the data by removing the noise from the individual drugs and used the indications for each drug. Here is that data by number of prescriptions and then by cost:

You can see the disruption caused by the brand name drugs which catapult PPI (ulcer/heart burn medications) from 5% of the prescriptions to 17% of the cost and take statins (cholesterol) from 9% of the prescriptions to 18% of the cost. Can you imagine how the chart looked before Zocor (simvastatin) went generic?

There are no insulins on the list, so I wonder if there other absences.

What does it say about the U.S. that 3 of the top 6 indications for therapy are pain, depression and anxiety?