Neutrophil gelatinase-associated lipocalin (NGAL) is a promising new biomarker of AKI.  While the cardiologists have troponins, and now highly sensitive troponins, nephrologists have been stuck using creatinine as a marker for AKI.  Creatinine has many flaws: at least 50% of kidney function must be lost before it even rises; it is highly dependent on age, gender, muscle mass, etc.; it does not distinguish between pre-renal, post-renal, and renal causes; and by the time it rises, the damage to the kidney is already done.  There is a lot of research devoted to finding a better marker, and maybe NGAL is it.

This review (and this more formal meta-analysis) discusses the evidence supporting the potential of NGAL as a marker for AKI.  In children, it appears to be a fantastic biomarker: whereas Cr bumped 1-3 days after cardiac surgery in kids, there was a 10-fold elevation in NGAL within 2-6 hours.  It was 100% sensitive and 98% specific.  It appears a bit less wonderful but still quite good in adults, with sensitivities generally ranging from the 70’s to the 90’s%, and specificities in roughly the same range.

There are a couple things to consider here: the diagnosis of AKI in these studies is made based on serum creatinine, which as we just discussed is a rather poor “gold standard.”  What if some of the “false-positives” were in fact not, and there was AKI without rise in Cr?  Or what if some of the “false-negatives” were in fact Cr elevations not due to AKI?  That’s the problem when you have a bad gold-standard.  It’s hard to really judge the new test.  I think the proof will be in the pudding: if NGAL elevations lead to more prompt treatment, or to novel treatments effective early in AKI but ineffective after Cr elevations, then clearly it would be a god-send.

Another comment in the article caught my attention: “[NGAL] performance compares favourably with that of troponin for the prediction of myocardial infarction during its clinical implementation period.”  I think looking for the perfect biomarker is probably to miss the point.  Troponin is one of the closest things we have, and that took years before it reached it’s current level of precision.  I think we’ll find that for AKI, this will be pretty similar: a good, but not perfect, biomarker that will be combined with some lesser biomarkers (analogous to CPK/CPK-MB) that will provide an answer.  Maybe not an irrefutable answer, but certainly a lot better than we have now.  And I suspect that much like troponins, with time NGAL (or some successor) will be refined to a point where we will finally have a gold-standard for detecting AKI.

First, I am always so impressed by the ACP advocacy efforts. Bob Doherty in particular is such an impressive speaker, and is always in command of the facts. It is reassuring to know we have such people looking out for us as physicians and for our patients.

A couple thoughts and impressions from the past 2 days:

-It was interesting to be there lobbying for the 5 year SGR patch only to watch it crumble apart on the very morning we headed to Capital Hill. The AMA effectively killed whatever chance it may have had of passing. I understand the AMA’s point that we need a permanent fix and not a temporary patch, but come June 1st we are back to, at best, a year-to-year situation. Since we got home, another possible fix is on the table–and one that preserves the “two bucket” approach championed by the ACP, which would allow for selectively higher payments to primary care.

-The Independent Payment Advisory Board (IPAB, or as it is known in Cupertino, iPab) can make recommendations regarding Medicare payments. Now, however, certain of these recommendations (notably, those affecting physician payments) take effect automatically unless Congress intervenes to stop them. This is not actually a bad idea in my opinion, but the law requires a super-majority in Congress to overturn the IPAB recommendations. This part is a very bad idea. I think the Senate has shown us nicely what happens when a super-majority is required.

-The 10% bonus to Medicare payments to primary care is a very good idea. However, there are some definitions problems. Specifically, to qualify a practice must earn at least 60% of income from primary care visits. It is not too hard to imagine how a practice that sees a lot of inpatients and maybe has a lab and an xray machine might earn 41% of income from non-office visits. And yet these are exactly the internists that we need more of–the ones still doing it all.

-Lastly, I was a little bit disheartened by the Congressional staffer panel this year. Always my favorite part, you usually get the idea that even if the rest of Washington has gone crazy, at least these 24 year-olds will still go out and get a beer together. But this year there did seem to be a little less congeniality than last year. The tone from all the politicians and staffers was a little more sharp this year.

Once again, it was a great meeting, and kudos to the ACP. To those interested in getting involved, go to the ACP website and follow the “advocacy” links. The easiest and yet very useful step is to sign up to be a Key Contact. You’ll get info about breaking issues and advice on how to lobby your representatives.

This is a sentiment voiced by many others, but it always leaves me puzzled. As a resident, I spend less time than I’d like at a computer. Call nights are spent in the ED, poking and prodding, both verbally and physically. Too many crosscover notes begin, “Called to bedside for…”. I often dream of a job as described by Dr. Verghese, where I sit before a computer without complicated family discussions, difficult histories, perplexing exams. In reality, I spend too little time at the computer, and then prior to rounds I sit down and furiously fly through electronic notes and old echo and cath reports, so that when I round with my attending I can explain that 4 years ago, the patient’s ejection fraction was 35%.

Is there some projecting going on here? To all the attendings out there: if you feel you are not spending enough time at the bedside, then that is a personal choice. Those of us at the tip of the spear seem to spend little time elsewhere. We are always happy to have company.

I recently saw a young woman who was admitted for a GI bleed. During her admission, she developed a fever and a zealous physician ordered blood cultures and a rapid influenza swab. Knowing that influenza was unlikely in this patient with no respiratory symptoms, I discontinued the influenza swab, but not before infection control swept in and tossed the patient into airborne respiratory isolation. An overly zealous nurse obtained the swab despite my cancellation. Not surprisingly for a patient with no respiratory symptoms, her rapid influenza was negative. I wrote an order to discontinue respiratory isolation. The next morning, there she was, trapped behind the crime-scene tape that crosses the doors of patients in isolation, with an empty box of N95 masks outside her door. I asked why nobody had removed her from isolation as I’d asked. The answer: since she’d been swabbed for flu, she had to serve 7 days in isolation.

Nevermind that this is not in accordance with CDC guidelines, which recommend a surgical mask instead of an N95 mask–a recommendation based on good evidence. The same guidelines recommend droplet precautions, not airborne isolation. This is also supported by evidence, such as an Annals of Internal Medicine article that found airborne transmission, if it occurs, is not “a frequent enough occurrence to be of significant concern when considering control measures for most clinical settings.” These two things are probably being overcautious, but they are harmful to nothing except my hospital’s bottom line. If they have the money to spend on N95 masks, I’ll wear them. If they have the negative pressure rooms to use, then they are welcome to use them.

I am concerned with the bigger question: is my patient harmed by being in isolation. The answer is yes. Studies have shown that healthcare providers are half as likely to enter the room of patients in contact isolation. But a generally well-done article in JAMA lays out the actual harms that come from isolation. Of note, patients in isolation:
        - have 2.9 times as many days without a recorded physician progress note
        - are 7 times as likely to have a preventable adverse event
        - are far more likely to express dissatisfaction with their care

As the study authors conclude, the benefits associated with isolating those at risk of transmitting infection within the hospital must be balanced with the known individual risks associated with placing a patient in isolation. In the case of my patient, even if the transmission rate of influenza was 100%, her risk of an adverse event from being in isolation was much higher than her risk of transmitting flu–given her very low risk of flu in the first place. These considerations are especially important when we are talking about 7 days in isolation for suspected flu, or for indefinite isolation for MRSA carriage. We have an obligation to the public health, but we cannot jeopardize the patient in front of us.

So where to turn? Based on ALLHAT, the first-line treatment recommendations became thiazide-type diuretics. In the US, this became hydrochlorothiazide (HCTZ). In Europe, this was bendrofluazide. The reasons these two drugs became the thiazides-of-choice is not clear. I have asked Google, but if it knows then it’s not telling. Neither was in ALLHAT, which is the study that drove the recommendations–it used chlorthalidone. But then again, I don’t know how atenolol became the beta-blocker-of-choice, either.

Thus, since the fall of atenolol, HCTZ has been the official first-line antihypertensive. As such, it has also been the comparator of choice when conducting new studies. But should it be? Back when I was starting kindergarten, the Multiple Risk Factor Intervention Trial (MRFIT) reported in 1982 a trend toward excess risk of cardiovascular mortality in patients treated for hypertension with thiazide diuretics. In the trial, 6 centers used chlorthalidone, and 9 used HCTZ. After 5 years, investigators noted a 44% increased mortality risk in the group treated with HCTZ versus the “usual care” group. This was not found in the chlorthalidone-using clinics, and all patients were changed to chlorthalidone. At study’s end, after 10.5 years, there was an overall risk reduction of 28%. Although this was a retrospective observation, it is, to say the least, interesting.

In 1995, a study comparing amlodipine to HCTZ found that “the use of HCTZ in doses of up to 25 mg daily is inadequate for ambulatory BP control in the elderly despite official recommendations.” Indeed, the studies showing significant beneficial effect for HCTZ used doses of 25-50mg, even 100mg: the European Working Party study, the MRC Working Party study, the MIDAS study, and the INSIGHT study.

Though guidelines have elevated thiazide diuretics (and thus HCTZ) to first line therapy primarily on the basis of ALLHAT, subsequent studies have exposed some chinks in the ALLHAT armor. The ANBP2 reported better outcomes in elderly patients treated with ACE inhibitors versus those treated with “thiazide diuretics”–that is, HCTZ. Most recently, ACCOMPLISH demonstrated superiority of a CCB+ACEI combination over a ACEI+“thiazide” (HCTZ) combo.

What do these studies mean? Do they suggest that the ALLHAT trial was wrong, or that it is (as I’ve heard it called) “Old Hat”? I recommend an excellent editorial discussing the ACCOMPLISH trial in the context of ALLHAT and other prior research. It suggests, as have others, that the problem is the term “thiazide diuretic,” suggesting all thiazides are alike. As one editorialist put it, if you’ve seen one thiazide diuretic, you’ve seen one thiazide diuretic. Chlorthalidone and HCTZ are actually quite different in their pharmacodynamics. First, chlorthalidone is roughly twice as potent as HCTZ. Second, the half-life of HCTZ is 8-15 hours after long-term use; it is 45-60 hours for chlorthalidone. I would argue that this is likely clinically significant. Chlorthalidone reduces ambulatory blood pressure more than HCTZ, and this is likely due to chlorthalidone’s longer duration of action. Since we tell patients to take their diuretics in the morning, when we check BP in the office it is well within HCTZ’s duration of action; at night, however, BP tends to increase. Is this relevant? Well, we have no prospective head-to-head trial, but as noted above, MRFIT suggests it is quite relevant.

So, does ACCOMPLISH say that ACEI+CCB is superior to ACEI+thiazide diuretic? Do these recent studies suggest that ALLHAT is wrong? I say no. I would argue, on the basis of the above-linked evidence:
        - that ACCOMPLISH reinforces prior evidence that HCTZ is the lesser sibling of chlorthalidone,
        - that ALLHAT is solid evidence that chlorthalidone should be our first-line thiazide,
        - and that no study has come out demonstrating the superiority of any drug over chlorthalidone as first-line treatment of hypertension.

This is an interaction that is increasingly recognized. Fluticasone is a substrate of CYP3A4, and ritonavir is a potent inhibitor of CYP3A4. This leads to decreased clearance of fluticasone and the potential for iatrogenic Cushings or adrenal insufficiency. The effect is most typically seen at fluticasone doses greater than 500mcg per day, and the time to onset of Cushingoid features is typically 2-3 months after drug initiation. Inhaled fluticasone (as in Advair) is a greater culprit than intranasal fluticasone (i.e., Flonase), but both have been implicated. Other inhaled steroids such as budesonide seem to be safer, probably because fluticasone is the most lipophilic and thus has the larger volume of distribution. Note that of the intranasal steroids, however, mometasone (Nasonex) behaves similarly to fluticasone and should also be avoided.

It is important to ask about ritonavir specifically when getting a medication history from patients. It is typically not used as an active drug, but rather to “boost” levels of other protease inhibitors. Because of this, it is sometimes left out of patient-reported HAART regimens. In the patient above, Combivir is a combo of 2 NRTI’s (zidovudine/lamivudine) and Kaletra is lopinavir plus ritonavir.

Cushings syndrome in HIV(+) patients must be distinguished from HAART-associated lipodystrophy. On physical exam, lipodystrophy will not have striae, and Cushings does not present with the peripheral lipoatrophy seen in HAART-associated lipodystrophy. Cushings should be strongly considered in patients presenting with the associated metabolic derangements of corticosteroid excess (such as diabetes and osteopenia / osteoporosis), with new or treatment-resistant hypertension, or with hypokalemia.

Although ritonavir, due to its potency in inhibition of CYP3A4, is probably the drug most likely to contribute to iatrogenic Cushings, other drugs inhibit CYP3A4 and should be considered. These include verapamil, clarithromycin, and the azole antifungals (especially itraconazole, which is especially potent). Most other protease inhibitors also are at least weak inhibitors of CYP3A4, as are ciprofloxacin and amiodarone. Some of these drugs (amiodarone and the azoles, for example) are so notorious for drug-drug interactions that most people carefully review the med list carefully for interactions before starting them. However, how often do you consider this before writing for 6 weeks of ciprofloxacin for osteomyelitis? Also, of the macrolides, clarithromycin is the most potent CYP3A4 inhibitor, and this should be borne in mind when prescribing prophylaxis for HIV patients.

Finally, megestrol (Megace), a progestin with some corticosteroid activity, can contribute to development of Cushings syndrome in patients on inhaled steroids, especially if they are also being exposed from another source as well (such as inhaled steroids). Sudden withdrawal from megestrol can also precipitate adrenal insufficiency, especially in acutely ill patients.

Anyway, I was bummed about missing Journal Club. The topic of the day is the recent mammography guidelines, and I was ready to pick a fight. I have been driven to distraction by the brouhaha over the new USPSTF guidelines. In particular, the politicization of these guidelines is infuriating to me. So since I missed my chance to vent at Journal Club, I am going to vent here. If the post ends mid-sentence, it is likely due to a plaster projectile.

To me, the first question is: why is everybody so surprised by these guidelines? I think that to show surprise about these changes is to announce that you haven’t kept up with the literature even a little bit. When last we left off, at the time of the USPSTF’s 2002 guidelines, the Swedish trials were the talk of the town. Looking specifically at the 40-49 age group, mammography was not beneficial. Largely based on these trials, the International Agency for Research on Cancer (IARC) concluded, in 2002, that there was sufficient evidence for screening women age 50-69 with mammography, but there was limited evidence for the efficacy of screening women age 40-49 by mammography. Based on the Swedish trials, mammography had a rate ratio of 0.81, with a 95% CI of 0.65-1.01. In other words, there was a non-significant reduction in breast cancer mortality of 19%.

Let me break for a bit to discuss statistics. This will be quick. I was an English major for good reason. But I want to be clear about one thing first: when I say “non-significant reduction in breast cancer mortality of 19%,” I am not saying that reducing breast cancer by 19% is not “significant” in the meaning of “important.” I mean it is not significant in the mathematical sense. Note the confidence interval: 0.65-1.01. A confidence interval (CI) are those values that, if we repeated the measurements over and over, we’d expect 95% of the outcomes to encompass. If all of those values favor a particular outcome, then we can be reasonably (but not absolutely) certain that the outcome is real and not a result of chance. In the case of the Swedish trials, the 95% CI includes values that favor no screening over mammography. At best, we can say there was “a trend” toward better outcomes with mammography, but we cannot be reasonably certain by the typical definition of “reasonable” used in medicine–that is, 95%.

Ok, so I probably butchered that explanation. Back to the stuff I understand. Since 2002, there have been 2 articles addressing mammography in patients age 40-49. The first, out of the UK, followed 160,921 women. The design was interesting: women turning 40 were randomized to annual mammography screening for 7 years or to no screening. They then had no screening for 3 years, and then were enrolled in the UK 3-yearly screening program. In this study, the point rate ratio was 0.83, with a 95% CI of 0.66-1.04. Again, a non-significant reduction of, in this case, 17%. Very similar to the Swedish studies (and suggesting that maybe there is something to this statistics stuff). The USPSTF also considered a follow-up to one of the Swedish studies, which found a point rate ratio of 0.79, with a 95% CI of 0.58-1.08. The p-value, for those who prefer it to CI, was 0.14. Not statistically significant.

What does all this look like in meta-analysis form (from which the USPSTF made their recommendations)?

Note that not one trial meets statistical significance. Put them all together and you barely get a statistically significant result. Conclusive? I don’t think so.

The truth is that none of these studies really answers the question. They suggest that maybe mammography might reduce mortality in women age 40-49 by something around 17-20%. But if we are honest, we have to admit that maybe mammography does nothing in this age group. Want to muddy things a little more? Take the Canadian National Breast Screening Study 2 (CNBSS 2). Unlike the trials mentioned above, it did not compare mammography versus no screening; it compared mammography plus regular clinical breast exams versus physical exams alone. 39,405 women ages 50-59 were enrolled. There were 107 deaths in the mammography group versus 105 deaths in the physical exam-only group. Null hypothesis–check. The risk ratio was 1.02 for mammography with a 95% CI of 0.78-1.33. Not surprisingly, mammography had many more false positives and identified many more small (and likely clinically insignificant) tumors.

So does mammography even add benefit to clinical breast exam (CBE) in the 50-59 age group? Maybe not. Does that mean mammography is equivalent to CBE? Not necessarily. As noted in a published response to the CNBSS, if mammography and CBE were equivalent, you would expect some added benefit of doing both. There is none. The conclusion of the commentator is that this suggests they are both ineffective.

Head hurt yet? I’m not done.

Suppose you aren’t willing to concede that mammography is a lousy screening tool. And after all, you say, what’s the harm? Well, overdiagnosis is the harm. First, let’s define the term. Overdiagnosis is the identification of a cancer when that identification does not affect the prognosis. (That may or may not be the “official” definition, but it is the spirit of it anyway.) Suppose cancer is found on a screening test. What does that mean? Well, if it’s a good test, it means you found a cancer that is curable, but would not have been curable if you didn’t do the screening test. But it can also mean:

1) The cancer is detected earlier on screening, but it would have been curable even if detected later clinically (i.e., mammography picks up the tumor earlier than CBE, but it is curable either way)
2) The cancer is detected earlier on screening, but it’s too late and can’t be cured anyway
3) The cancer is detected earlier on screening, but it’s slow growing or destined to regress or what-have-you, and the patient is destined to die of something else before dying of the cancer

You can argue that #1 and #2 fall into the “no harm, no foul” category. I’d argue that they in fact represent a significant and unnecessary expense. But in either case, screening does not help. And think about this: as our treatment options for breast cancer improve, unless our screening tests improves proportionately (it hasn’t), it will become less an less beneficial. If we ever get to a point of being able to cure all breast cancer at any stage, then screening becomes useless. We’re not there, but we are improving quickly. But let’s focus on cancers detected on screening that fall into category #3. These will likely result in some degree of harm. Imagine a tumor that is found on mammography, biopsied, and found to be invasive. Best case scenario, there is a lot of terror, an uncomplicated lumpectomy, lots of further studies, and more terror. Let’s put some numbers on this, and for those numbers, let’s turn to the Cochrane Reviews. They published a review of the risks and benefits of mammography this year (2009). They estimate an overdiagnosis rate of 30%. They also note that screening programs increase the mastectomy rate by 20%. Lumpectomies increased by 71% in the Netherlands when screening was introduced. These 2 facts alone suggest that there are many mastectomies and many more lumpectomies being done that would not be needed otherwise. Do most of them save lives? Almost certainly. But consider a couple things. You could estimate that, if the overdiagnosis rate is 30%, then 30% of those mastectomies are unnecessary. I admit that does not necessarily follow. But surely some of them are unnecessary. And ask this question: if mammography is supposed to pick up cancers earlier, why would mastectomy rates go up? Even though the percentage of cases of carcinoma in situ treated in the US by mastectomy declined from 71% in 1983 to 40% in 1993, the total number of mastectomies increased almost 3-fold. In the UK, after screening programs were started, mastectomies for invasive cancer increased by 36% and for carcinoma in situ they increased by 422% over the period from 1990 to 2001! Now, say that without mammography, some women might be diagnosed at a late stage and no mastectomy is done because they are too far gone. But most are identified clinically, eventually, and would get a mastectomy. How can mammography increase mastectomy rates by such a profound degree unless some (many?) of them are due to overdiagnosis? And of course, overdiagnosis is going to be much more common among women in their 40’s than those in their late 50’s.

We fixate on physical harms, but I’d argue that psychological harms are essential to consider as well. In the same Cochrane review, 1/3 of women with false-positive tests were still undergoing testing and had not been declared disease-free at 6 months. 6 months! That is a long time to think you might have a fatal disease. Women who had an abnormal mammogram but were then declared cancer-free after biopsy or other studies were twice as likely to suffer psychological consequences 3 years later as those who had a normal mammogram. No physical harm, but the psychological harm lasts.

Overdiagnosis is not talked about very much. In journal articles, it is often downplayed, and more so when the author has a stake in screening programs. But it recently hit the mainstream press, and there was a bit of an uproar. “Why don’t doctors talk about this?” became a frequent question on comment threads. Well, kudos for the USPSTF for considering overdiagnosis in their guidelines.

Okay, so there is the data. Do you find the question of mammography for women in their 40’s to be straight forward? Me neither. Now let’s look at the actual words used by the USPSTF:

“The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient’s values regarding specific benefits and harms.” [emphasis mine]

How is this controversial? The data to support universal screening just isn’t there. The test just isn’t that good. You need a certain pre-test probability before it is of benefit, and your 40 year-old non-smoking woman with no family history of breast, prostate, or ovarian cancer just isn’t high enough risk. When the signal is too low, all you’ll get is noise. But should you screen the smoker whose brother has prostate cancer? Of course, and the guidelines agree. To say that the benefits of universal screening of women ages 40-49 clearly outweighs the risks is to ignore the evidence. And when the benefits are likely small, and the risks are real, it is reckless to suggest anything other than making it an individualized decision.

So, what to expect from this?  Well, hopefully there will be several updates per week, some with little more than a clinical pearl I came across or was reminded of, and some with a more in-depth case discussion.  Hopefully this works for me as a medical journal, and hopefully somebody else gets some small benefit out of it as well.  So long as the first part is true at least, I shall keep this up.

For those wondering what my reference point is, I will be focusing on hospital medicine.  However, anything I find interesting is fair game!