We are fighting multiple myeloma one step up the mountain at a time

We are Moving Mountains for Multiple Myeloma (MM4MM)

Yes, I get that it makes no sense but neither does "Race for the Cure." But today in order to raise money to advance science we need to do dramatic feats of physical exertion. I am going to the bottom of Everest. Yes, going to the top of Everest would be cooler but no I'm not doing that. The bottom is the goal.

In the nine years that I have been maintaining this blog I have never asked for money. Today this changes. I am making "the ask." Please donate to the Multiple Myeloma Research Foundation in my name. Need to raise $10,000. I get 30,000 page visits a month. Let's knock this out.

Here is the link for donating

The MMRF is a 501(c)(3) organization so your donation is fully tax deductible in the U.S.

The MMRF is a really cool, outcomes oriented, research foundation that has successfully brought drug after drug to market for multiple myeloma. I feel really good about raising money for them. They get 4 stars on the charity navigator.

Here is my full pitch letter:

Help me get to the bottom of Mount Everest!

I know everybody else dreams of the top, but I’m the kind of kid that when my dad asked me what I wanted to be when I grew up I told him “co-pilot.”

In the spirit of wanting to be a co-pilot, I am now aspiring to get to the bottom of Everest, AKA Basecamp, elevation 18,000 feet. Keep in mind that non-pressurized aircraft are limited to an altitude of 12,500 feet.

I am part of an expedition for the Multiple Myeloma Research Foundation. Why is a nephrologist working with the myeloma foundation? Well besides the obvious, I get to go to Mount fricking Everest, multiple myeloma plays a constant and recurring role in my job as a kidney doctor. One of the first symptoms of multiple myeloma can be foamy urine. The foam is from protein and these patients are often referred to me. My job puts me right at the beginning of the long journey of myeloma. I am the person that explains that those bubbles in the urine were actually serious, and that they have cancer. Unfortunately, the protein also can clog the kidney and many of these patients require dialysis during their treatment. So again I get to play a role in the lives of these patients.

There have been tremendous advances in myeloma therapy during my career. Outside of HIV, no other deadly disease that has seen such impressive improvement during my career. One of the reasons is the Multiple Myeloma Research Foundation. The MMRF is an amazing organization that has invigorated myeloma research and helped bring 10 myeloma drugs to market.

 

I am asking you to help me raise $10,000 for the MMRF. The whole Everest trip is funded by a grant from Takeda Oncology, so none of your donations will be buying my ramen, it all goes to the Multiple Myeloma Research Foundation (rated 4 stars by Charity Navigator for the last 11 years). Learn more about MMF here.

I’m asking you to make a donation.

Help me get to the bottom of Everest. 

Go to this link to make a donation.

Joel

Polycythemia and a Horseshoe kidney

This is a reported complication.

Nice review of polycythemia, with full text: Current applications of therapeutic phlebotomy

Mention of this complication in a textbook of hematology.

Patients with Horseshoe Kidneys have increased risk of renal cell carcinoma, so make sure you rule this out before just sending the patient for phlebotomy.

FERE: Fractional excretion of random electrolytes

Magnesium:

• 142 controls: 1.8% (range 0.5-4%)
• 74 hypomagnesemic
• Extra-Renal origin 1.4% (range 0.5-2.7%)
• Renal origin 15% (range 4-48%)
• Authors conclusion: >4% per cent is indicative of inappropriate renal magnesium loss

Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia.

Potassium

• 312 normal subjects: 8% (range 4-16%)
• 84 hypokalaemic patients
• Extra-renal origin: 2.8% (range 1.5-6.4%)
• Renal origin: 15% (range 9.5-24%)
• Authors conclusion: >6.5% per cent is indicative of inappropriate renal potassium loss

Fractional excretion of potassium in normal subjects and in patients with hypokalaemia.

Renal Physiology You Tube Videos

I'm trying to collect some you tube videos for med students. Send me your favorites. No hour long lectures. Only looking for lessons that are shorter than 10 minutes.

This was good.

I like this one

I'm a Ruz fan.

Competerized 3-D model serves no purpose. Just confusing.

Again I feel the 3-D computer modeling serves to confuse more than educate.

Khan? Is there anything this guy doesn't know?

We live in the future

Yesterday, the consult team was evaluating a patient in the ICU and I asked to see the x-ray. A fourth year medical student started scrambling with his iPad to bring up the image. After about 15 seconds he apologized for how slow it was and then a few seconds later the image resolved.

And I just started laughing.

It was just over decade ago that we started daily rounds down in radiology to go over all of the films for our service. Well not all the films because a third of them were always missing, usually the missing ones were in the OR or still on the radiologists light box carousel.

This looks ancient. It was 1999.

I still remember that uncomfortable shame that came from having to tell my attending that I couldn't get the films. Rounding in the ICU was great because there was a satellite reading room attached to the unit so we could just duck into a room to see the images fresh from the developer. I remember being alone in the University ER when a dying man came in. The story sounded like an acute MI but I was worried about an aortic aneurysm and I was so busy putting in lines and starting pressors I couldn't get to radiology to take a peak at the mediastinum. Luckily a co-resident wandered by and was able to sprint to radiology to get the answer.

Fast forward to today and I have a kid apologising that his handheld wireless device, that is capable of displaying decades of lab results, all the notes and consults, is going to take anther few seconds to display the x-ray that was taken an hour ago.

We didn't get flying cars, but we did get a lot more than just 140 characters.

Big anion gap. Big knowledge gap.

I just saw one of the biggest anion gap of my life and I don't know the cause. Worse yet, the patient had this occur a few months ago, also with no explanation. So I want to figure out what is going on before admission number three.

Patient presented to the ED obtunded and was unable to give a cohesive history. The admission labs:

So lets calculate the anion gap.

Add the bicarb to the chloride 

subtract that sum from the sodium

 and you get OMG!

I mean

This comes in below the gap of 70 I took care of in 2011 (presumed metformin-induced lactic acidosis) but edges out the more recent 51 from propylene glycol from 2015. So the way I like to tackle these mysterious anion gaps is to create a Gamblegram named after pediatrician James Gamble who invented the concept in 1939. The idea behind the Gamblegram (and behind the concept of the anion gap itself) is that the total number of anions must equal the total number of cations, otherwise if you touched blood, it would give you a shock. Then we graph out the cations and anions that we know, while leaving "unmeasured or unstated" cations and anions as a box. This patient looks something like this:

Looking at the numbers, the gap gets so large because not only is the bicarb so phenomenally low, but they have a pathologically low chloride and a sodium which is bumping up gainst the upper limit of normal. Additionally the potassium is a bit low, shrinking the other cations box.

We have an ABG done a few minutes after the chemistries were drawn:

• pH 6.94
• paO₂ 179
• pCO₂ 6
• HCO₃ 1

Then we hit that with Winter's formula: 1.5 * 1 = 1.5 plus 8±2 gives a target CO₂ of 7.5 to 9.5, just a bit higher than the actual pCO₂ of 6. So this patient has a metabolic acidosis with a slight respiratory alkalosis. But who can fault them for hyperventilating with a pH south of 7.

So with a massive metabolic acidosis and a ginormous anion gap, you should be itching to order a toxic alcohol screen. But first check for other causes of an anion gap metabolic acidosis:

• Aspirin: less than 2.0 mg/dl (works especially well with the concurrent respiratory alkalosis)
• Acetaminophen: less than 5 mcg/dL
• Lactic acid: 9 mmol/L
• Ketoacidosis: This hospital doesn't do real time serum ketones. So we didn't have data acetone, betahydroxybutyrate or acetoacetate levels. However the U/A showed ketones at 20 mg/dL 

So if we start to fill in the gap:

• A normal gap is 12 mmol/L
• Lactate is 9 mmol/L
• The phosphorus is 7 mg/dL. Four of that is included in the normal gap, the extra 3mg/dl converts to 1 mmol/L
• That comes to 22, leaving an unknown gap of 31. Some of this will presumably be filled by ketones, acetoacetate and betahydroxyburyrate. 

Next step is to look for an osmolar gap, because if you aren't thinking toxic alcohol you aren't wired to be a nephrologist, toxicologist or critical care doc. The serum osmolality is 342. Calculated osmolality:

I know that your shitty medical calculator does not include ethanol or if it does it divides it by 4.6 not the correct 3.7. For crap calculators see MedScape, GlobalRPh, (QxMD and UpToDate don't even include alcohol?!). Even Wikipedia gets this right. Get with the program, get MedCalcX or use MD+Calc.

So the osmolar gap is 342-321= 21. High but not very impressive, especially compared to the anion gap in the stratosphere.

The thing to understand about toxic alcohol's, anion and osmolar gap is that they move in opposite directions. Ethylene glycol (antifreeze) and methanol (fuel, incompetently distilled spirits) are both neutral alcohols. They are osmotically active so they contribute to the osmolar gap, but since they are not anions they do not contribute to the anion gap. So early after ingestion the osmolar gap is high but the anion gap remains low.

Then the toxins are metabolized (initially and most importantly by alcohol dehydrogenase) into toxic downstream metabolites. Many of these metabolites are acids that lose a proton, and thus become anions. So after metabolism the anion gap will climb as neutral alcohols are converted into anionic acids. Interestingly, the osmolar gap falls. Even though the metabolites are low molecular weight and osmotically active, they do not contribute to the osmolar gap, because the equation includes them in the calculated osmolarity. When you multiply the sodium by two, you are covering all anions in solution. Since the acids are anions they are covered by the calculated osmolality and don't contribute to the gap.

So our patient with the big anion gap and the modest osmolar gap could just be a late presentation of a toxic alcohol. Once that has happened and the osmolar gap has retunred to normal. Even if there is a large anion gap it is probably too late to intervene with fomepizole to block alcohol dehydrogenase. Once the osmolar gap has closed the toxin has moved downstream of the alcohol dehydrogenase.

But our patient still had an osmolar gap. So we gave fomepizole and dialyzed the patient. The next morning the osmolar gap had closed and the anion gap was nearly normal. We stopped the fomepizole and dialysis. On the third hospital day we got back the toxic alcohol screen. 

• Acetone 31 mg/dl
• Methanol: not detected
• Ethylene glycol: not detected
• Isopropanol 12 mg/dL

Isopropanol, is commnly called isopropyl alcohol, rubbing alcohol. It will increase the osmolar gap but is not converted to an acid and does not cause anion gap metabolic acidosis. Divide the level by its moleculatr weight, 60, and then multiply by ten to convert "per dl" to "per liter." So the level of 12 accounts for 2 of our abnormal osmolar gap of 21.

The Acetone is interesting. It is also not a charged molecule so will not account for the anion gap, but it is in equilibrium with two charged molecules that can generate an anion gap: acetoacetate and beta-hydroxybutyrate. 

I looked but could not find the expected ratio of acetone to the other two ketones in order to extrapolate from the acetone level to the concentration of the anions. I couldn't find a reference, but I found a number of documents that said acetone was a definite minority. So if we estimate that each ketones is at 2-3 times the concentration of acetone we have a 20-30 mmol/liter combined concentration of acetoacetate and betahydroxybutyrate. (Molecular weight of acetone is 58, so 31 mg/dl is 5.3 mmol/L). This essentially fills the unknown gap.

Could this just be alcoholic ketoacidosis? The patient had a triglyceride level of 600 mg/dL which is consistent with alcoholism? The serum glucose on admission was 57, also consistent with alcohol induced ketosis. 

I personally am not very satisfied, because I see drunks all the time (at work, not socially) and nion gaps this high are very unusual. I personally think there is some other ingestion stimulating the massive ketosis. Looking for ideas.

Notes: We have an oxoproline level cooking, but the negative acetaminophen level makes this less likely in my mind. No, we didn't send a D-lactic acid level.

Gastrorenal syndrome

Nothing can accelerate a scientific career like harnessing the work of lots of scientists by creating a new paradigm for thinking about old research. We have long known that gastric bleeding and kidney disease are often seen together, but no one has been able to harness them together in a cohesive theory, So in the hopes of greatness (and many international speaking gigs), I introduce a schema to understand the many manifestations of renal dysfunction and gastric bleeding: Gastrorenal Syndrome (GRS)

GRS Type 1. 
Acute kidney injury leading to gastric bleeding.
Acute kidney injury can causes increased sympathetic nervous system activity, increased cortisol release and alterations in the platelet function. All of these contribute to an increased risk of upper GI bleeds. In addition drugs, such as NSAIDs, increase the risk of both AKI and GI bleeds. If the kidney gives out before the stomach you have GRS type 1. If the stomach starts bleeding before the kidney goes let me introduce you to GRS type 2...

GRS Type 2. 
Gastric bleeding leading to AKI.
It has long been noted that sudden drops in hemoglobin can cause ischemic acute tubular necrosis. But previous authors have failed to properly place this in the syndrome of gastrorenal disease.

GRS Type 3. 
Chronic kidney disease leading to gastric bleeding.
CKD has long been recognized as an important risk factor for GI bleeds and now we have a schema to organize that in its proper place.

GRS Type 4.
A history of GI bleeds and peptic ulcer disease that leads to CKD.
This was just a hypothetical entry until the blockbuster news last year that chronic use of proton pump inhibitors is associated with CKD. Now we know that the mythical GRS type 4 is no figment on anyone's imagination, but rather a real entity.

GRS Type 5. 
A separate disease leading to both AKI and gastric bleeding. Think of the acutely ill patient with sepsis who develops AKI and a GI bleed. Don't make the rookie mistake of seeing two separate diseases, you are actually witnessing CRS 5!

Look for many review articles in Seminars of Nephrology and other closed access journals in the near future.










This post is getting a bit of traction on social media and I fear some might not get the joke. See this link for my feelings on cardiorenal syndrome that I was trying to spoof.

The beautiful futility of journal club

Hot take: journal club shouldn't change the way you treat patients because most articles exciting enough for journal club need additional data, replication and time to mature. By the time the data is compelling enough to justify changing your practice the data comes via a boring meta-analysis that you read and remark, "I knew that, we read about it in journal club like 3 years ago."

See: Medical Reversal: Why We Must Raise the Bar Before Adopting New Technologies Link