Ad hoc blood pressure lecture

I am attending on the dialysis service in December and the residents requested a lecture on hypertension. This was a sharp group so I decided to do an update on the literature and go through four papers in the session. It went well. We had lots of great discussions and answered a lot questions.

SPRINT. We talked about the impressive results but really focused on the very selective patients population and how it was not consistent with a lot of patients we see in clinic. We also focused on how they assessed blood pressure and how different it is than standard blood pressure assessment.

The next study was HOPE-3 shows that when you apply what you know from SPRINT but use a standard blood pressure assessment and pair it to a less sick population you get a negative result.

Then we looked at PATHWAY-2 to put add some evidence to the question of how should we treat resistant hypertension.

Then we finished with “Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials” a fascinating meta-analysis that looked at dose response curves, and side effects. Really interesting paper. H/T Ricky Turgeon PharmD. The conclusion from the data is that adding additional drug classes at lower than standard doses results in a nice blood pressure improvement with a clean side effect profile.

Other suggestions that didn’t make the 40 minute cut:

— Ross Nesbit (@RossNesbit) December 30, 2016

Treatment of Hypertension in Patients 80 Years of Age or Older

Agree this is an important study.

@kidney_boy Bit late to this but ASCOT-BPLA

— Annette Neary (@feline_charm) December 30, 2016


Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial

I almost feel that a trial that has Atenolol in the control arm is practically a placebo. That drug never reduces events. I think the official tag line is “Atenolol: when all you care about is reducing the number on the dial.”

@kidney_boy ACCORD BP (lower not always better, esp. In Diabetics) since SPRINT included non-Diabetics. Would also include HYVET

— James Pritsiolas, MD (@Nephro_Doc) December 29, 2016

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus

This is the opposite side of the SPRNT coin. Low blood pressure appeared to be of no benefit and possibly harmful (Table 2). Nice reduction in stroke though (Figure 2). 

@kidney_boy … and Symplicity HTN-3

— Indranil Dasgupta (@idasgupta7) December 29, 2016

A Controlled Trial of Renal Denervation for Resistant Hypertension

The mother of all medical reversals. Great study. Totally upset a runaway freight train of interventions. To me this shows that industry sponsored trials (when designed with the intension of FDA approval) are not marketing shams but can add clarity to medical knowledge.

Why I am going along with the ABIM shakedown

So I received the e-mail telling me it’s time to pay the ABIM or I will get the dreaded “not participating in maintenance of certification” addendum to my board certification.

This is horrible. If you make people take a massive high stakes exam to be board certified for the next decade then the ABIM should not effectively revoke that board certification (or at least put it in doubt) because I am not participating in continuing medical education in the way they see fit. I am an adult and can study and maintain my skills as I see fit. Taking, and passing the recertification exam proves I am responsible for my own education. It makes me so angry and it really feels like it is there just as a money grab. Don’t tell me that I passed a 10 year recertification exam and then discount your own exam after  couple of years with that damn asterisk.

That said my whole career is built on certification. The privileges of being a doctor are due to a complex interplay of private and public certifications. Much of the edifice of nephrology is based on certification and hospital privileges preventing just any person or even any doctor from providing dialysis. I feel that since I receive so much from these certificates it is a bit hypocritical to pick and choose when I want to participate. I have cast my lot with the certification process so I will continue to participate.

Additionally, even though I have am angered and feel ripped off by the ABIM protection racket, when I try to explain the controversy to non-doctors they don’t get it. People put so much trust in doctors and they are rightly terrified of getting a bad one. This is why Top Doctor issues of the local glossy magazine are so popular. People want a good doctor and intuitively know that their ability to recognize quality from personal interactions or or other superficial experiences it limited. People want systematic mechanisms in place to weed out poor ones and make sure all doctors are maintaining a level competency. Unfortunately, I feel that ABIM is not a good mechanism for this aim. But people are naturally suspicious when they hear that doctors are complaining about how onerous a certification process is. I think their first inclination is, “Yes! Hold those doctors to task.” And while physicians fret about the nightmare that occurs to individuals that fail to maintain their board certification, the public feels the opposite, and are thankful that somebody is at the wheel trying to maintain the quality of the physician workforce.

So I am going to pay my pound of flesh and continue to work with ABIM to reform the system rather than leave it entirely.

Update:

Imagine if a year or two after graduating college, you get a letter from your alma mater telling you, that even though you completed all of the coursework and payed all the tuition bills, everytime someone inquires into if you actually graduated they were going to tell them “Yeah, but we don’t think he is so serious about maintaining his skills and have reason to doubt his commitment.” We would be happy to change this message to simply “Yes, he graduated” if you pay us $353.00 every year. It sure would be a shame not to get full credit for all the work you’ve done getting that degree, and compared to how much money you earn because of the degree, $353 is just not that much money.”

I remember feeling screwed that my board certification, unlike people just a few years older than me, would require constant recertification. Ten years between board exams is not too onerous, but then after that they made the deal worse still, and now I need to recertify every ten years and pay them yearly, so ABIM doesn’t smear my name in the public.

Maybe I should just pray they don’t alter the deal any further.

Update. Even better video:

.@kidney_boy @rcamd @EleanorLederer This video better encapsulates the @ABIMCert ‘deal’ https://t.co/FhH8JiDVC1

— Just Some MD (@justsome_md) March 8, 2017

Diuretic Infographics

For the second time I in the last month I was looking for these graphics n PBFluids and for the second time I couldn’t find them. I was sure I had posted them, but I hadn’t.

So here are my loop and thiazide diuretic infographics. Enjoy.

Nephrogenic diabetes insipidus and carbonic anhydrase inhibitors

Nephrogenic diabetes insipidus (NDI) is incredibly difficult and frustrating to treat. If the cause of NDI is loop diuretics, hypokalemia or hypercalcemia, it is a trivial problem, however in patients with congenital NDI or lithium induced NDI the treatment options are limited and pretty ineffective. The standard game plan is administering thiazide-type diuretics paired with a low salt/low solute diet. Here is the page from The Companion:

I think the first question is one of my favorites in the entire book.
Recently there has been some noise that carbonic anhydrase inhibitors maybe the way to go in lithium induced NDI.
Lithum causes NDI in two stages. In the first stage, lithum induces a down-regulation of the aquaporin-2 channels. The second stage comes from loss of the aquaporin-2 expressing principal cells of the collecting duct. To compensate there is an increase of alpha-intercalated cells.
The theory that HCTZ improves NDI through volume deficiency first took a hit in 2014 when Anne Sinke, and company showed that mice with lithium induced NDI but without the thiazide sensitive sodium-chloride co-transporter (NCCT) could still reduce urine volume in response to thiazide diuretics.
Let that sink in for a moment…mice that do not have the thiazide sensitive NCCT respond to thiazides as expected in regards to lithium induced NDI. This finding required an explanation and the authors suggested that this could be due to the carbonic anhydrase activity of thiazide diuretics. 
Yes, I know that thiazides reliably cause metabolic alkalosis, but despite that they have some minimal carbonic anhydrase activity that is uncovered in the NCCT knockout mice. According to this site, thiazides were initially designed to be carbonic anhydrase inhibitors, and then found to have NCCT antagonism activity. (Fun fact if you ask google about the thiazide’s effect on carbonic anhydrase the top hit is from David Goldfarb (@Weddellite) back from his basic science days.)
Back to the carbonic anhydrase story. Carbonic anhydrase is critical for bicarbonate reabsorption in the proximal tubule because it allows hydrogen secreted by the Na-H exchanger to combine with filtered bicarbonate to form CO2 and water. The CO2 is able to freely able to enter the proximal tubule cell where it combines with a hydroxyl group to reform bicarbonate. 
The authors concluded that by blocking carbonic anhydrase, there was less sodium reabsorption in the proximal tubule leading to activation of tubular glomerular feedback lowering GFR.
This lead to a second series of experiments where the same team reproduced the same reduction in urine volume but this time with acetazolamide, rather than HCTZ. The authors also thought there was a second mechanism based on acetazolamide’s ability to decrease lithium entry into principal cells of the collecting duct (similar to amiloride) and/or a reduction in intra-renal prostaglandin synthesis.
Fast forward to November 2016 and we have an interesting letter in the NEJM regarding a human patient with NDI that was admitted for a craniotomy. Post-operatively he developed recalcitrant hypernatremia with severe polyuria rising to 12 liters a day. 

…we administered acetazolamide to a patient with severe lithium-induced nephrogenic diabetes insipidus that was resistant to hydrochlorothiazide treatment and other measures…

The team used 500 mg of acetazolamide bid to take his urine output from ridiculous to merely absurd. Compelling data.

What does a medical student do when they have a renal question? Introducing #AskRenal

Yesterday’s post and interaction has been bouncing around my skull all day. First of all I was blown away by the discussion generated by the simple question of “What does aldosterone do?”

@niaree @kidney_boy Take a look at this summary, as well. Part of an epic review of the evolution of aldosterone. https://t.co/xILmMwHSeG pic.twitter.com/b4mdjIcOhn

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@niaree @kidney_boy Last paragraph of this review in Cell 1983 suggests that’s not a new problem. Can be bought cheaper, I think, tho pic.twitter.com/XlAMgn9CiC

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@niaree Yes! You can request ‘Hunger for Salt’ be delivered for pickup at EHSLhttps://t.co/ZIKBkWnfSu

— Eccles Library (@EHSLibrary) December 8, 2016

And then I started to think about the possibilities. I imagine that Niaree has a lot of friends with nephrology questions. And I have a lot of friends that are nephrology nerds just bubbling with answers.

I’m thinking if there was a hashtag that could be used by medical students struggling with renal phys and renal pathophys that resulted in an immediate answer from nephrologists all over the world we could leverage the always-on nature of Twitter to demystify the black box that is the kidney.

Plus getting the pulse on the questions that keep hanging medical students will make us all better teachers.

So why don’t we try this. 
Medical students brings us your confusion, your riddles, your frustrations with renal. Your mass of ambiguity yearning for clarity. Throw off your darkness for enlightenment. #AskRenal is here to clarify your journey.

No Salt Humans

Great Twitter moment tonight when a medical student confessed ignorance of aldosterone and an aldosterone basic scientist piped in with what he finds beautiful about aldosterone.

Renal Week 2: I’m still not sure what aldosterone does. Seems important, though! 🤔🤔

— Niaree Davis (@niaree) December 1, 2016

@niaree @kidney_boy Na is tiny&goes right thru glomerulus. Need means to effect controlled reabsorption or you’ll be sodium-free in 2 hours😱

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

@kidney_boy @niaree Signific of aldosterone highly dependent on sodium intake? Not sure Yanomami man could survive 5 mg lisinopril, ca 1970?

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

I had no idea what Yanomami man was but Brian was right there:

@kidney_boy @niaree Here’s an old paper describing the Yanomami population that is interesting https://t.co/XzhZ1AGfTp

— J. Brian Byrd, MD MS (@thebyrdlab) December 8, 2016

So the paper is available for free here and it shows a kidney homeostatic system performing in ways that I would have guessed were impossible.

A 24-hour urine sodium of 1 mmol. No fricken way!

I give you table 4:

Anybody want to hazard a guess at what the giant unmeasured anion in the urine is?
Phosphate?
Bicarbonate?
Probably bicarb, especially when you take a gander at their aldo levels:

I wonder if these indians suffered from all of the ill effects of aldosterone thrown about?

Treating mild hyperkalemia

Somewhere along the road to becoming a doctor med students develop the hyperkalemia insulin reflex. See an elevated potassium give 10 units of IV insulin and 25 grams of D50. Yesterday I saw this done for a potassium of 5.6.

No. One. Dies. From. A. Potassium. Of. 5.6.

But there is morbidity from the insulin glucose antidote.

These guys from Rush University Medical Center looked at the risk of hypoglycemia from the standard 10 units of insulin followed by 25 grams of glucose. They found 13% of ESRD patients developed a glucose south of 60 mg/dl.

Remember the kidney both metabolizes insulin and is a source gluconeogenesis, so dialysis patients are naturally more prone to hypoglycemia.

 Love me some table one.

The patients that developed hypoglycemia were less likely to be diabetic, and had a lower glucose. In response to this study the authors suggested an alternative regimen of increased glucose monitoring and an additional 25 grams of dextrose:

Similar data was found in a study by Schafers. Schafers followed that study with this one, which suggests that weight based insulin dosing 0.1 units/kg up to 10 units could reduce hypoglycemia by about half:

What is truly terrifying is if some people start trying to really drive the potassium down with Sterns’ recommendations from KI:

Sterns suggests 6u bolus f/b 20u/hour insulin + 60 g glucose/hour for acute hyperkalemia in KI review https://t.co/vUTgibCyxE

— Swapnil Hiremath, MD (@hswapnil) April 14, 2016

Also good factoid, there is less hypoglycemia if you add albuterol to insulin and glucose.

Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects

Let’s be careful out there and stop treating inconsequential hyperkalemia, let’s save our toxic antidote for truly toxic potassiums.

At what potassium would you give insulin + glucose?

— Joel Topf, MD FACP (@kidney_boy) December 6, 2016

When a non-clinician tells you AKI is simple, prepare for disappointment.

Acute kidney injury (AKI) is hard.

Things that seem like they should work often don’t. Just ask Perry Wilson.

And even the most predictable cases of AKI are resistant to intervention. Look at bypass surgery. We know days in advance the time and place the AKI will occur and despite that foreknowledge, like Cassandra, we are powerless to prevent the AKI. Same with contrast administration (or not). Same with AAA surgery. We have been unable to meaningfully reduce the rate of AKI in any clinical circumstance.

AKI is a tough nut to crack.

So when I read about this guy, Mustafa Suleyman (Twitter), telling the public that,

“There are around 1,000 people a month dying needlessly. This is a huge hidden killer. It costs more than breast cancer care in the UK and [AKI] is super simple to prevent.” 

I’m insulted, like we must be idiots that we haven’t fixed this yet. And thank-god the computer scientists are here from Google to finally cure AKI for us.

Turns out the National Health Service is implementing a system at The Royal free Hospital to speed alerts to doctors so they can react quickly to signals of acute kidney injury. The headlines being generated from this project are amazing:

The company providing artificial intelligence is DeepMind, a Google company. The product that detects AKI early enough to avoid it is Streams.

Maybe we should excuse the visionary of an artificial intelligence company. The medical director of the Royal Free should be a bit less grandiose and more evidence based. What did he have to say?

Stephen Powis, medical director at the Royal Free said, “We know that a quarter of deaths from acute kidney injury are preventable if clinicians are able to intervene earlier and more effectively.”

Boy, that sounds like data that comes from an interventional trial where warnings were given to some clinicians and others did not receive them and the RR for AKI was 0.75. Unfortunately, this study has never been done. When a similar study was done by Perry Wilson they found no effect at all from early warnings. When I asked Med Twitter if they knew where this data came from I was given a few old retrospective trials.

@ddfirl @kidney_boy NCEPOD report says up to 30% preventable https://t.co/e6hbpIqKQY ref: prospective observ’n data: https://t.co/0HjUx0rTUM pic.twitter.com/SIQqzrx20V

— Benjamin Stewart (@drbstewart) November 23, 2016

Nothing prospective. Nothing to justify the certainty of Dr. Powis. The 25% comes from a report produced by NCEPOD called Adding Insult to Injury. The report attempted to analyze all of the deaths for 3 months in 2007 due to AKI. They failed to capture surgical patients and they did not get the records on 40% of the cases they requested.

As part of this examination of the failures they asked experts that reviewed the case files if the AKI was avoidable and they said yes it was in 14% of the cases. I’m sorry, but the distance between a reviewer believing an episode is avoidable and an AKI case actually being avoidable is more than a casual step, let’s call it a major leap. Remember that reviewers were only reviewing patients with mortal outcomes. Given that, the reviewers knew of the subpar outcome, I’m not surprised the reviewers found lots of substandard care:

Maybe I am jumping the gun and the Deep Mind notification system, Streams has been prospectively vetted and shown to improve outcomes. I also concede that it is likely that the system can improve the number of AKIs but that isn’t and shouldn’t be the sole goal of the system. AKI is an intermediate outcome. The system should be judged on its ability to reduce mortality and here I am skeptical. I suspect the AKIs that are simple to avoid are not the ones driving the high mortality levels.

I believe the Deep Mind people have this type of model of AKI:

In this model, all the different etiologies of AKI feed into a single pool of undifferentiated AKI and measures that reduce the incidence of any of the causes of AKI will reduce the fraction of patients that die of AKI.

I think the correct model of AKI is more like this:

In this model each etiology of AKI leads to mortality in it’s own lane. So changes in the incidence of AKI from volume depletion can only reduce the already low mortality from that cause of AKI.

I look forward to seeing the results of this project and hope that they are measuring the outcomes and plan to publish their prospective and interventional data.

Confirmation bias, cognitive dissonance, and contrast nephropathy

I have been following the research of McDonald which repeatedly showed no signal of contrast nephropathy when looking at large databases.

Controlled contrast medium-induced nephropathy studies demonstrate a similar incidence of AKI, dialysis, and death between the contrast medium group and control group.

This was just a curiousity that felt like the work of magician because no matter how many different ways that McDonald et al tried to prove there was no contrast nephropathy, I had seen it with my own eyes. I had seen young people with a normal creatinine who were completely stable go for a contrasted CT scan and then spiral into renal failure in subsequent days. No one could convince me that this was incidental renal failure. Renal failure just doesn’t happen like that.

The best I could do to explain away the work of McDonald was to say that she is a radiologist so it must be biased in favor of her procedure/specialty. I know this is weak sauce but the I had seen it with my own eyes could not be silenced. Then Chertow. Here was the most prominent nephrology clinical trialist of our time coming to the exact same conclusions as the radiologists.

…the incremental risk of AKI that can be attributed to radiocontrast is modest at worst, and almost certainly over- estimated by patients, physicians, surgeons, radiologists, and other decision-makers.

I have been trying to reconcile this cognitive dissonance and this is where I am. The decision to use changes in creatinine to define contrast nephropathy results in a definition that captures lots of false positives.

Definition of contrast-induced nephropathy (CIN): impairment of renal function defined as either a 25% increase in serum creatinine (SCr) from baseline or 0.5 mg/dL (44 µmol/L) increase in absolute value, within 48-72 hours of intravenous contrast administration.

Note that unlike definitions of other entities like hepatorenal syndrome, there is no exception if there is alternative explanation for the renal failure. Any patient with sepsis, hypotension, and a complete breakfast of aminoglycosides, ketorolac, and ramipril that happens to get a contrasted CT scan followed by a bump in the creatinine is another case of contrast nephropathy. Though being admirably sensitive, this definition is wildly non-specific.

So the key question in evaluating the definition of contrast nephropathy is what proportion of cases are real cases of contrast nephropathy and what numbers are incidental AKI that happen to occur after contrast exposure. In other words how many of those contrast nephropathies are false postives. To reconcile my experience and Chertow’s data I have shifted my position from being mostly true positives with a small amount of noise to mostly noise with only a few cases of true contrast nephropathy.

Once you accept that the the majority of cases of contrast nephropathy are just incidental cases of AKI, other facts start to come into focus. For example, look at the risk factors for contrast nephropathy:

  • CKD
  • Diabetes mellitus
  • Advanced age
  • High contrast dose
  • NSAIDs
  • ACEi
  • Heart failure
  • Balloon pump
  • Volume depletion
  • Hypotension
  • Shock

How many of those are also risk factors for AKI in general? Outside of contrast dose, I’d say all of them.

How about the interventions we do to reduce contrast nephropathy:

  • Avoid diuretics
  • Avoid NSAIDs
  • Stop ACEi/ARBs
  • Give IVF (and 0.9 NS is better than 0.45 NS)

This looks like a pretty good recipe for avoiding AKI in general.

Why is this important? Well for one I think our research is lying to us. I have been surprised on multiple occasions that the patients that get contrast nephropathy don’t fit the model of the high risk patient and likewise patients that are set-ups to get contrast nephropathy don’t. Our models are so overwelmed with incidental AKI that they do not give us a good idea of the people who are truly at risk of real contrast nephropathy.

I wonder, if we were to do a careful analysis of contrast nephropathy cases where we excluded every case that could have an alternative explanation of AKI, to produce a cohort of people with a very low rate of false positives. How different would the risk factors for contrast nephropathy look like in that cohort? I suspect contrast nephropathy would look more like an idiopathic condition.