Monday, August 21, 2017

Two more OUWB questions

Hi Dr. Topf,

I had a question regarding the Macula Densa.  When reviewing your powerpoint on volume control, you have a slide that said there is only one osmoreceptor (Hypothalamus) because osmolarity across the body is the same at all times.  I’ve had some confusion regarding the Macula Densa, but from what I understand it is also an osmoreceptor (sensing Na+ in the tubule), which would make sense because the tubules are the only part of the body where osmolarity is different.

I thought that the Macula Densa would affect GFR and stimulate the release of renin from the Juxtaglomerular cells, but that would seem to affect volume (RAAS System maintains volume), so my question is why does the macula densa (which senses Na+) controlling volume and not Osmolarity?
Good question.

So the macula densa is a major part of a process called tubuloglomerulo feedback

As the name implies this is important for balancing GFR with tubular reabsorption.

If you had excess GFR and limited tubular reabsorption, people could literally pee them selves to death in minutes

Think about the math, you have 3 liters of plasma and filter 125 ml of it every minute. so it would only take 24 minutes to completely filter all of the plasma. if you are not constantly reabsorbing 99% of that very rapidly you could become volume depleted and suffer from cardiovascular collapse.

Tubular glomerular feedback prevents that. At the end of the thick ascending limb of the loop of henle, there are chloride receptors as part of the juxtaglomerular apparatus. If there is too much filtration and not enough reabsorption, the excess chloride will bind these receptors and cause a release of intra-renal signals that decrease GFR by adjusting the dilation of the afferent and efferent arterioles.

So yes there are receptors that bind chloride and you can think of them responding to the various concentrations of chloride (like an osmoreceptor) but they are not involved in volume regulation or osmoregulation, but rather the safe running of the kidney to prevent a person from accidentally peeing themselves to death.

Hope this helps

Hello Dr. Topf,

I hope you are doing well. I had a few questions in regard to your last lecture at OUWB. I was wondering if you could explain the pathophysiology behind euvolemic hyponatremia caused by hypothyroidism and adrenal insufficiency. Also, in the case of SIADH, whay wouldn’t the person have hypervolemia if there is a constant reabsorption of water? Is there a pathophysiologic explaination for this as well? I could not find any answers online.

So the key here is to remember that volume is determined by total body sodium and that SIADH is generally Na in = Na out. So they are in sodium balance and will not be volume overloaded.

You are right that these patients will have excess water, but much of this water disappears into the intracellular compartment and the excess volume can not be picked up clinically (by exam or by conventional blood and radiology tests). Yes there is excess water.

We try to reserve terms like hypervolemia for excess total body sodium, and this is not found in SIADH.

Hope that is helpful.

Friday, August 18, 2017

OUWB Sodium and Water Questions

For the sixth year I have had the privledge of teaching at OUWB. When I teach I get e-mail questions from the students. I respond to the students by e-mail but also post the questins and answers here so all the students get the advantages of the questions.

Caller one you are on the line...

"Long time listener; First time caller. Some of the M3s were telling us that last year, they were confused on this Team Based Learning exercise because they learned hyponatremic means low water/volume but originally they thought it meant low salt, and hypovolemic means low salt but they thought it meant low water/volume. 

Could you explain? A lot of us are confused now..."

The conflation of volume and osmolality is always confusing.

Hyponatremia means a low sodium concentration.

Hypovolemia means a low total body sodium (literally the total number of grams of sodium in the body). Hypovolemia does not say anything about the concentration of that sodium.

That low total body sodium may be at a high a high or low concentration depending on what the total body water is.

For example heart failure is a common cause of hyponatremia. These patients have edema and other evidence of volume overload. This is a combination of volume overload and hyponatremia. Increased total body sodium, but even great increase in total body water.

Patients with severe diarrhea also can develop hyponatremia. In this case they are volume depleted, decreased total body sodium.

And lastly, patients with SIADH, say from small cell lung cancer, are euvolemic and have a normal total body sodium*.

You can’t equate the two, just like saying that a bowl of soup is salty doesn’t explain how big the bowl is. If the soup is salty but you have only a spoonful, there is not much salt.

Hope this is helpful.

Next caller...

"Hi Dr. Topf,

I hope your day has been going well! I was reading over the TBL preparatory material for tomorrow and came across a point that was slightly confusing. 

Could you please clarify what exactly was meant by the following: 

"Clinicians often characterize hyponatremia by the volume status, hypovolemic hyponatremia versus hypervolemic hyponatremia. It should be clear that both of those two seemingly different causes of hyponatremia, share a single patho- physiologic explanation."

I'll hang up and take my answer off the line."

Thanks for calling. Great question. This was covered in this slide from my second lecture:

The point of the slide and that both hypovolemic (on the left) and hypervolemic (on the right) cause hyponatremia by the same physiologic mechanism:

1. decreased perfusion (from heart failure in hypervolemic and volume depletion in hypovolemic)
2. Release of ADH (due to the low perfusion, not a high osmolality)
3. Decreased urine output
4. Water intake > urine output

Is that clear?

Next caller...

Hello Dr. Topf,

Please, call me @Kidney_Boy.

Hope you're doing well. I really enjoyed your lectures today. I was studying for our upcoming class on Friday where we are going to be quizzed on a lot of the same information and I became a little confused. In the TBL article (pg 12) there is a figure and a paragraph that says glucose induced hyponatremia is a type of pseudo-hyponatremia. However it also defines pseudo-hyponatremia as a decreased serum sodium with a normal serum osmolality. 

Is the glucose induced factitious hyponatremia is a kind of pseudo-hyponatremia ? If so how can it be a pseudo-hyponatremia when the glucose causes an osmolality imbalance?

Thank you so much. 

This one is one me. The TBL document needs to be updated This is just a nomenclature issue. 

There is some ambiguity on whether glucose induced hyponatremia can be called pseudohyponatremia, there is some support for it and I used to be in that camp (in fact I wrote a whole book about fluid electrolytes waving the glucose induced pseudohyponatremia flag) but most people limit the term pseudohyponatremia to just the high protein and high lipids causing the lab error (sometimes called a lab artifact), and separate out the high osmolar causes under a different category (factitious hyponatremia).

So I would study what I taught in lecture today. Understanding concepts is more important than knowing the specific names.

Obligatory blog post about the subject (see the segment after the Update):

Hope that helps.

That really clears things up for me! Thank you so much! 

That's all we have time for. Until next time...

Thursday, August 10, 2017

Great article on Visual Abstracts

Timmothy Aungst is a pharmacist who has been writing about the intersection of technology and healthcare for years. I first encountered him when he was on the handheld health applications beat for iMedicalApps. We met in person at the Boston Med 2.0 in 2012.
He recently wrote an insightful and in-depth essay on Visual Abstracts. Unique from other articles he went through the process of creating his own visual abstract in the article. The whole thing works quite well.

Here is his #VisualAbstract. Outstanding first effort.

He interviewed me for the article and included my CANVAS Visual Abstract. He asked me for my perspective on the future of visual abstracts and I provided an uncharacteristically cynical quote. We'll see how prescient this turns out to be:

❝ We are going to go through a rough stage where enthusiasm for visual abstracts outstrips technical ability or understanding of what the goals of the abstract are. You will get journals asking for authors to supply them and they will have no idea what they are doing or what is really being asked for, so they will provide poor facsimiles of visual abstracts. This really has the potential to slow down the entire movement. ❞

Thursday, August 3, 2017

The New Visual Abstract Editorial Team at CJASN

A year ago I had not even heard of a visual abstract.

Today I'm part of the visual abstract editorial team for CJASN.

I'm proud that nephrology, represented by CJASN, AJKD and JASN, has moved swiftly to adopt this new medium.

The team is working collaboratively and each of us is signing off on all of the designs so we can continue with #DesignThinking without breaking confidentiality. I'm really proud of the work we have done so far:

Tuesday, August 1, 2017

Why you should donate to the Multiple Myeloma Research Foundation

One thing that bothers me are disease organizations that use the fear of the disease to raise money to treat the well. This happens when breast cancer organizations raise money to "raise awareness." You know what? No one with breast cancer needs their awareness raised. Similar to this but more subtle is raising money to promote and pay for screening. Again this is using the fear of the disease to treat people who do not have the disease. to treat people more like the board members and employees of a charity that likely do not have the disease.

If I'm going to work for a disease charity, I want to work with a charity that helps people with the disease. This is true in my work for the NKF of Michigan (though I have noted a recent, and troubling trend away from this core mission).

When I looked into the Multiple Myeloma Research Foundation (MMRF), the benefactor of my current fund raising push for my trip to Everest Basecamp, one of the facts that stood out was the claim that the MMRF had been instrumental in bringing nine drugs to market for the treatment of multiple myeloma.


I read this and I thought "bullshit!" That just too much. A charity would be delighted and lucky to have just one drug come to market in a decade. To have 9 hits in 20 years begs credulity.

Since that initial skepticism I have done some research, talked to scientists, and I am a believer.

The MMRF is an amazing organization that is doing charity and medical research right and deserves your dollars. Let's reward a charity for saving lives and making a real difference rather than just getting football players to wear pink gloves for a month.

The origin story of MMRF is remarkable. Kathy Giutsi, at age 37, was a pharma executive on the fast track up the corporate latter. Then she was diagnosed with multiple myeloma. She made some pretty dramatic changes in her life (including going through IVF to have another baby!) and started the MMRF.

As a patient it isn't surprising that Giutsi was focused on novel treatments and one of the first treatments she funded was Velcade. A drug that turned out to be particularly effective for her variety of myeloma. She was instrumental in funding the discovery and approval of the treatment for her own disease. It sounds like a Hollywood script. The MMRF was also instrumental in developing Revlimid the other breakthrough myeloma drug of the last twenty years.

I spoke with a myeloma scientist and he described how MMRF helps him. The MMRF acts as an interface between commercial pharma companies that have promising new drugs and myeloma doctors that have patients. When this scientist works with the MMRF he is able to write the protocol and design the trial. When he works with drug companies outside of the MMRF, he follows the protocol provided by industry. Talking to him it became clear that the MMRF valued independent, researcher-driven studies looking for the Truth rather than drug company trials that looked for FDA approval.

Another tenet of the MMRF is sharing research advances the field. While a lot of pharma research never goes beyond the corporate firewall, research done with MMRF money is shared widely and timely.

This is how you move science: empower individual scientists motivated by truth not profits. Share the discoveries quickly. Lubricate the wheels with money and social connections. The MMRF does it all because it is motivated to find a cure, not promote its own name, screen the healthy, or spread disease awareness.

Here is an article on the MMRF from the New Yorker in 2008.

2011 article on MMRF by Matthew Harper.

Join me in supporting the MMRF by donating here. All of the money goes to research, none of it goes to support my Nepalese Trek to Everest Basecamp.

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