Using an iPhone for capturing urine microscopy

From the NEJM:

The authors describe their technique:

When microscopy revealed a field of interest, the camera was placed about 0.5 to 1.0 cm over one of the eyepieces, allowing optimization of the image and light intensity by means of the camera's digital display. The auto-focus and exposure features generally produced a circular image surrounded by a black rim...

Can't wait to try this.

Hat tip Pediatric Nephrology

Article on aging I want to spend some time looking at

From the American Scientist: Aging: to Treat or Not to Treat?

Patient called me with a blood pressure of 170

He has resistant hypertension that has been well controlled since we added spironolactone. He reported that his systolic blood pressures were between 170 and 205 over the last three hours. In the morning his blood pressure was 120 and for the last week he had been getting blood pressures of 115 to 135, trending toward the lower end of that range.

I told him that I wasn't worried about the isolated spike in blood pressure. The goal of therapy is to get the average blood pressure down and that chasing individual isolated episodes of hypertension becomes a hopeless game of whack-a-mole.

The treatment of hypertension is like trying to change the climate, not control the weather.

What do you do when they get this phone call? Do you chase after elevated blood pressures with prn clonidine? Is there an evidence based approach to this?

How many cancers have you caused from ordering CT scans

It feels like if a patient coughs they get a CT angiogram to rule-out pulmonary embolism. How many patients would defere that test if they had to sign off on the following chart:

Makes you think twice regarding the CT for stone-profile that some patients get yearly "just to make sure the Urocit-K is working."

Hat tip to Academic Life in Emergency Medicine blog.

If you are giving a commencement speech be original, don't steal

Arrogant? Stupid? Both?

Incredible story today comes from the University of Alberta Medical School where the dean, Phil Baker, plagiarized Atul Gawande's Stanford commencement address from 2010 during U of A's own graduation ceremony. My favorite part is the students using iPhones to discover the intellectual property theft during the speech:

"A couple of the students recognized the term 'velluvial matrix,' which is in Mr. Gawande's speech," said class president Brittany Barber. "They Googled it on their phones.

For anyone to think they could rip-off a high profile author in this day and age is the height of arrogance and or stupidity.

Epo, anemia and the lack of placebo controlled trials

By a mistake of communication I was scheduled to give the anemia talk at a recent chronic kidney disease symposium. I would have never selected this topic on my own. I work with Robert Provenzano, one of the Gods of Anemia. Fortunately, this was a happy accident. I loved researching and writing this presentation. The whole experience was an important lesson on the value of working out of your comfort areas.

The anemia saga is well known to all nephrologists and is covered in depth in my presentation but let me recap my version of the story.

Life before Epo was pretty bad. the average dialysis patient received a transfusion more years than not. On the Eve of Epo the transfusion was rate was 16% per quarter!

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter is a 98% reduction in transfusions. Revolutionary. And this doesn't even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

I was in college when this happened and it's a little hard to imagine how exciting that must have been.  The introduction of Epo launched a million observational trials that all pointed in the same direction: 

Where you found higher hemoglobins you found better patient outcomes. 

It almost didn't matter what outcome you were interested in: hospitalizations, mortality, regression of left ventricular hypertrophy, quality of life, fatigue score. It didn't matter, everything was better with higher hemoglobins. I suspect the community was seduced by the observational results but for what ever reason the amount of randomized controlled trial data that emerged was laughably small. By 2007, Epo was eating up 1.8 billion Medicare dollars. It should have been the best studied drug and instead it was among the least studied.

I tried to find Henry Paulson's signature but had to settle for George Bush's.

Here is the table from K/DOQI anemia recommendations where they summarized all of the RCT data from the birth of Epo through May 2006 (apparently it omits a single 2005 study).

8 Epo vs Epo studies and 3 placebo controlled trials, 1 placebo controlled trials in pediatrics

The paucity of placebo controlled trials is shocking. No one demonstrated that higher hemoglobin targets had a mortality benefit or regressed LVH compared to placebo. This would not be so problematic if the Epo vs Epo studies had been positive, but those too were negative trials. So we are in the awkward position, a quarter century after the introduction of EPO we cannot conclusively state that the drug does any more than reduce transfusions and improve quality of life. All the mortality reductions, cardiovascular disease protection amount to observational-backed hype (one small rct (N=38) study did show a reduction in LVH).

Favorite slide from the deck

Part of me is outraged but another part understands how difficult it would be randomize dialysis patients to placebo. I couldn't, in good faith, expose trial subjects to the transfusions, fatigue and weakness that being randomized to the placebo-arm would entail. It fails my personal "Grandma test" (i.e. Would you feel comfortable enrolling your grandma in a placebo controlled trial of Epo? No). I understand that and forgive the dialysis researchers; however I am a little disturbed to witness how in the pre-dialysis CKD population the same pattern of relying on observational data. In CKD these is no transfusion epidemic that needed to be derailed, there is no profound fatigue turning patients to zombies. We had an opportunity to do the right studies to figure out if this expensive Nectar of Thousand Oaks really helped. The paucity of placebo controlled and randomized controlled trials in pre-dialysis patients is embarrassing.

Reading this editorial by Marc Pfeffer crystalized this critical mistake. I spent a fair proportion of the presentation laying out how statins evolved from being used in only the sickest patients to larger and larger populations and how at each step placebo controlled trials were used to prove efficacy. Not every step was a win, statins for heart failure failed, but the key is that cardiologists know that statins don't improve heart failure because they tested it with two (1, 2) placebo-controlled trials.

Why is nephrology lacking the randomized controlled trials that have defined the huge advancement in cardiovascular disease over the last 25 years?

• It isn't due to the severity of illness, the first placebo controlled trial of ACEi in heart failure used a cohort with 40% mortality at 6 months. 
• It isn't timing, ACEi for heart failure was developed and proven at the same time as the introduction of Epo.

I don't know the why but I have a couple of theories. One is the richness of the retrospective data in nephrology, brought to us by the USRDS, blinds us to the importance of prospective data. This could explain why are repeatedly burned by observational studies, see: kT/V, vitamin D, and binders.

The other theory is that, unlike statins and ACEi where there are many vendors producing drugs in the class of interest, there is a total monopoly in the field of ESA. You want to increase the hemoglobin you need to buy Epogen. No generic, no competing ESA. In the ACEi market, having enalepril as the drug studied in the CONSENSUS and SOLVD trials paid huge dividends to Merck. Having in-class competition lead to commercial support of critical research. Amgen had no need for this because the US Patent Office gave them a monopoly. A monopoly that seems to last forever. Why is it that every other drug from the late 80's is generic: omeprazole, captopril, enalepril, benazepril, metformin, simvastatin, etc. Even drugs from the 90's are now generic: losartan, lansoprazole. 

Epogen stands alone without generic competition. And unfortunately, largely without placebo controlled trials to back-up mountains of hype.

The deck can be found here: Keynote | PDF

The most difficult decision: Palliative care

I was peripherally involved in a patient with end-stage heart failure. We were consulted for hyponatremia. The patient had a sodium on 120 which we helped increase to 130. During our involvement, the family was wrestling with choosing palliative care. The patient was frail with advanced dementia.

The patient ultimately died in the hospital before being made comfort care. The family was relieved that he passed. I was struck by the question, that if the family was so relieved that he passed why was it so difficult to decide on palliative care.

In all the intensity of care conversations I have been involved in, I can't remember the principal asking the family to imagine how they would feel if that got a call from the hospital that their loved one had passed. And then add, that if the feeling is one of relief, that hospice, or DNR, or palliative care, is probably the right decision.

I need to get this font

Inspired by the title credits from Dr. Strangelove: Strangelove typeface

Here are screen captures of the title credit sequence:

Not "Death by PowerPoint" but "Death Star by PowerPoint"

I love this scene in Star Wars because it is pretty rare in movies to see a formal lecture. The presenter, General Dodonna, knocks it out of the park.

What if the Dodonna used Powerpoint?

Garr Reynolds from Presentation Zen deconstructs Dodonna's presentation style and compares it with contemporary powerpoint presentations. FYI, anyone who wants to do a better job creating and delivering presentations should be reading Presentation Zen.

Here is a movie with the same idea from YTMND:

Mixed acid-base disorder and altered mental status

An 80 year old woman was readmitted to the hospital with mental status changes. She was recently discharged following successful treatment for heart failure and associated fluid overload. Her discharge medications were as follows: (You know the joke: senior asks the intern, "What medications is she on?" And the Intern looks up and says, "uhm, all of them.")

She was brought to the ED with a week history of increasing confusion and weakness. The patient had some shortness of breath but this was typical for her baseline.

Initial labs:

The ABG showed:

• pH: 7.47
• pCO2: 71
• paO2: 74
• HCO3: 51

1. First look at the pH
1. It's elevated so this is a alkalosis
2. Look at the bicarbonate and the pH
1. If they both are moving in the same direction it is metabolic
2. If they are moving in opposite directions it is resiratory
3. Here the pH and bicarb are up, so it is metabolic
3. Put the two together and identify the primary disorder:
1. Metabolic Alkalosis
4. Calculate the predicted pCO2 from the bicarbonate
1. Calculate how far the bicarbonate has increased, this is the delta bicarbonate
2. Take two-thirds of the delta and add it to 40, the normal pCO2
3. In our patient the bicarb has risen from 24 to 51, a delta of 27, two-thirds of that is 18, so the pCO2 should be 58 +/-2
5. Is there a second primary disorder affecting the pCO2?
1. Compare the predicted pCO2 to the actual pCO2
2. If the actual pCO2 is lower than predicted, the patient has an additional respiratory alkalosis
3. If the actual pCO2 is higher than predicted, the patient has an additional respiratory acidosis
4. Our patient's actual pCO2 of 71, is way higher than the predicted 58+/-2.
6. The complete interpretation of the ABG is: a primary metabolic alkalosis with an additional primary respiratory acidosis

The ED diagnosed her with acute hypercarbic respiratory failure, and blamed the mental status changes on CO2 retention. She was started on bipap and admitted. The following day her pCO2 improved to 50 but she had persistant confusion. At that point we were consulted for acute renal failure, and noted that she had severe hypercalcemia, calcium of 14.7 mg/dl.

Her phosphate was 1.9 and subsequent work-up showed a PTH of 20., with normal 25 OH and 1,25 OH vitamin D.

On the basis of a combined metabolic alkalosis, acute renal failure, normal PTH and elevated calcium we diagnosed her with Milk-Alkali Syndrome, and started her on IV normal saline and SQ calcitonin. We did not give steroids or bisphosphonates. Over the ensuing four days her calcium drifted down to 10.1. On the third day her sensorium cleared.

Our patient seems to perfectly match the modern form of Milk-Alkali Syndrome or Calcium-Alkali Syndrome using Patel and Goldfarb's suggested nomenclature. The calcium and alkali were both supplied by calcium carbonate. Additionally she was on a thiazide-type diuretic which decreases calcium excretion. The classic 1930's form of Milk-Alkali Syndrome was associated with high phosphorous levels while the contemporary form has hypophosphatemia. The principle difference comes from the source of calcium:

• In classic milk-alkali syndrome the patient is calcium loaded from milk, which is very high in phosphorous (370-450 mg per 8 oz)
• In contemporary milk-alkali syndrome the calcium carbonate provides the calcium and also acts as a phosphorous binder to prevent dietary phosphorous absorption.

According to Patel and Goldfarb, the hypophosphatemia is more than just a spectator, it's integral to the modern disease. The low phosphorous stimulates conversion of the storage form of vitamin D (25 OH D) to the active form, (1,25 OH D) which further enhances GI calcium absorption:

Low phosphate levels stimulate the renal metabolism of calcitriol and, consequently, absorption of calcium by the gut. Levels of 1,25-hydroxyvitamin D in patients with the calcium-alkali syndrome, of course, are generally low in the setting of hypercalcemia, although some are in the low- normal range and perhaps inappropriately high. These latter levels may depend on previous exposure to vitamin D supplementation, because vitamin D is often added to some over-the-counter calcium preparations, but more epidemiology is needed to clarify this exposure.

Editor snark, I love the sentence: "Levels of 1,25-hydroxyvitamin D in patients with the calcium-alkali syndrome, of course, are generally low in the setting of hypercalcemia, although some are in the low- normal range and perhaps inappropriately high." So the levels arer either low, normal or high. Thanks for clearing things up.

The contemporary modern patient is typically female, and post menopausal. Other susceptible populations include cardiac transplant patients, pregnant patients, and those with calcium-rich food-fetishes (reported in anorexic nervosa patients).

Though the alkali and calcium are typically exogenous, diuretic-induced alkalosis can contribute to the condition, and doubly so, if the diuretic is a thiazide which decreases renal calcium losses. NSAIDs contribute by lowering GFR.

The Ca sensing receptor (CaSR) in the thick ascending limb of the loop of Henle binds calcium and binds it more avidly with alkalemia. Binding of the calcium sensing receptor shuts down the ROMK channel which decreases sodium reabsorption and increases urinary loss of calcium. Hypercalcemia, by activating the CaSR, acts like Lasix.

The loop-diuretic effect furthers volume deficiency, which, along with direct calcium-induced vasoconstriction, worsens the renal failure. Volume deficiency also stimulate calcium reabsorption in the proximal tubule.

Increased tubular calcium stimulates TRPV5, the principle calcium transporters in the distal nephron, decreasing renal calcium losses and furthering the hypercalcemia. The TRPV5 is also enhanced by the alkalosis.

Volume expansion with sodium chloride is the bedrock of therapy.

Do not miss the excellent and short review in JASN.

PBFluids is three

I'm such a bad parent. I forgot PBFluids birthday. The first blog post was May 30th 2008. 1,098 days ago. This is post number 390. The volume has tappered off recently but i still have the blogging fire in my belly I just have been working on some other projects: meaningful use, grand rounds, fellow teaching, and an upcoming primary care symposium.

It's been a fun trip. Here's to three more years of blogging!

Fructose, hypertension and CKD: an update

Today, I gave grand-rounds at William Beaumont Hospital Royal Oak. I gave the fructose-uric acid lecture I gave in January of 2010.

Over the last 16 months, the science has continued to move forward without any hiccups. Additionally, data supporting direct renal toxicity of fructose and uric acid has matured. This latest version of the lecture adds a section on CKD including a summary of both randomized-controlled-trials examining allopurinol to reduce the progression of chronic kidney disease.

The lecture is available in the under the lecture tab.