Month: August 2017

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OUWB Starling forces question


I was hoping I could ask you a few questions. I’m finding there is a lottttt of contradictory information.

  1. According to starling forces, decreased plasma oncotic pressure should increase GFR, but according to nephrotic syndrome, decreased albumin will cause edema and overall decrease GFR. Which one should I believe? 
  2. In general, it’s said that AT2 at low levels dilates the afferent arteriole to increase GFR, but at high level it constricts both efferent and afferent to decrease GFR. However, the SNS, which stimulates renin, constricts all arterioles in the body as well as activates the RAAS system. How does that work? Is the SNS more immediate until the aldosterone system is ready to say okay go ahead and dilate the afferent I’m ready to take up the water anyway? 
  3. This is a very basic question but sometimes I have moments of self doubt and this is one of them: So we always say edema is fluid buildup in ISF due to increased hydrostatic or decreased oncotic pressure (like nephritic syndrome hypoalbumineia) right? So why does fluid build up in ISF as opposed to go inside the cell where I guess technically there is more stuff to pull it in? 
  4. How does K suppress ammonia genesis? 

Thank you very much!

Let’s take these one by one,

NUMBER ONE
Nephrotic syndrome and GFR. Don’t connect those neurons. Proteinuria does not cause an immediate and hemodynamic change in GFR that is clinically meaningful. Yes, you are right that lower oncotic pressure should increase GFR, but those increases in GFR will be trimmed by tubuloglomerular feedback so that in the end there is not a meaningful change in GFR. Likewise the nephrotic syndrome will cause fluid to leak from the blood vessels decreasing effective circulating volume lowering renal plasma flow. However, once again these changes in volume are small enough that the kidney easily compensates with changes in AT2, PGE, filtration fraction, etc so that GFR remains stable.

Over a long time, proteinuria causes chronic kidney disease and decreases renal function, but not by the mechanisms you described.

Of note the model you are talking about with nephrotic syndrome causing fluid to leave the blood vessels and that resulting in decreased perfusion of the kidney is a model called underfill hypothesis of edema in nephrotic syndrome. Most nephrologists now ascribe by the overfill hypothesis which states that the primary abnormality is not loss of fluid from the capillaries from the decreased albumin, but increased sodium absorption by the diseased kidney. This results in volume overload and that causes the edema.
NUMBER TWO
As I understand it, angiotensin is only a vasoconstrictor. The proximal tubule is dilated by prostaglandin E. In volume depletion there is release of renin which activates angiotensin 2 (with help of angiotensin converting enzyme). Angiotensin 2 vasoconstricts both the afferent arteriole and efferent arteriole. But since the afferent arteriole is so much bigger to begin with, after the angiotensin 2 induced vasoconstriction the resistance in the afferent arteriole is less than the resistance in the efferent arteriole, this serves to increase the intraglomerular pressure, forcing more plasma through the glomerular slit membranes and increasing the filtration fraction and maintaining GFR in the face of volume depletion.
And yes the SNS is more immediate and the renin angiotensin aldosterone system is a bit slower.
NUMBER THREE
Where fluid builds up depends on what is being altered. In nephrotic syndrome, the (underfill) theory states (I’m an overfill believer) that decreased plasma albumin lowers the oncotic pressure drawing fluid from the interstium back into the capillaries at the venous end. This means more of the fluid remains in the interstium leading to edema. The oncotic agent of note here is albumin which determines the flux of fluid between the interstitial and plasma compartment.
In order to shift fluid between the intracellular and extracellular compartments you would need to change sodium and potassium which are the chief osmotically active particles of interest between those two compartments.
NUMBER FOUR
Hyperkalemia causes potassium to shift into the cells. To maintain electroneutrality hydrogen leaves the cell. One cation in, one cation out. The loss of hydrogen ions makes the cell alkalotic. This rise in pH tricks the proximal tubule cell into believing the entire body is suffering from metabolic alkalosis and since ammonia generation is used to increase hydrogen excretion, and correct metabolic acidosis, metabolic alkalosis shuts down ammonia generation.
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OUWB Non-anion gap question

Where does the chloride come from.

XXXXX and I had a question following the Acid-Base workshop. What is the origin of the increase in chloride ions in patients with NAGMA due to GI or renal causes?  

Thanks, 

 

So the key here is not to think of the body as static. As patients lose bicarb in the stool or in the urine, this will result in volume depletion which will be compensated for by renal retention of sodium and yes, chloride.

Great review of non-anion gap metabolic acidosis here:

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OUWB Euvolemic Hyponatremia question

Hello Dr. Topf,

I hope you are enjoying your weekend. I had a question in regards to one of your lectures. I was wondering why there is a low level of Uric acid in euvolemic hyponatremia but not in hypervolemic or hypovolemic hyponatremia. Also, how is it that Na taken in equals Na excreted in euvolemic hyponatremia?

All the best,

 
So why is there a low level of uric acid with euvolemic hyponatremia? Let’s first look at what happens to uric acid in the other causes of hyponatremia, namely hypovolemic and hypervolemic. In both of these situations the kidney is experiencing decreased perfusion, either from absolute volume depletion (diuretics, diarrhea) or perceived volume depletion from pump failure (CHF) or fluid maldistribution (cirrhosis and nephrotic syndrome).
In these volume depleted states there is an increase in the filtration fraction, i.e. more of the plasma that enters the glomerulus is actually filtered. This is how the kidney compensates for a decrease in renal plasma flow while maintaining GFR, it increases the fraction of fluid that is filtered.
A consequence of this, is that the oncotic pressure in the blood leaving the glomerulus is higher because more of the fluid (but none of the protein) has gone down the glomerular drain leaving the plasma in the efferent arterioles with a higher oncotic pressure.
This plasma then enters the vasa recta where it surrounds on the proximal tubule. Here the increased oncotic pressure pulls more fluid back.
This is an ideal situation. The increased filtration fraction maintains GFR in the face of decreased renal plasma flow, and the increased filtration fraction results in enhanced reabsorption of fluid in the proximal tubule limiting fluid loss in situations where patients have decreased perfusion.
Uric acid handling is complex and not fully worked out.
It appears that there is both uric acid secretion and reabsorption in the proximal tubule.
Functionally, uric acid clearance tracks with renal perfusion:
  • Decreased uric acid clearance with decreased renal perfusion
  • Increased uric acid clearance with increased perfusion of the kidney

This is similar to what we see with urea. The following description of urea handling gives a model that will work for uric acid, though the truth of uric handling is much more complex.

The key with urea is that it’s handling in the proximal tubule tracks with total fluid reabsorption in the proximal tubule.
With volume depletion, increased filtration fraction causes increased oncotic pressure in the vasa-recta increasing urea reabsorption in the proximal tubule.
In volume overload, decreased angiotensin 2 decreases sodium reabsorption resulting in less fluid reabsorption and less passive reabsorption of urea  so increased urea loss in the urine and lower serum urea.
Now what happens in euvolemic hyponatremia.
Sodium in equals sodium out. This means that these patients do not have a primary volume abnormality as we see in the hypovolemic and hypervolemic patients. Because of this their sodium regulation volume regulation system is not stressed, they are at homeostasis with regards to body sodium. When you are in homeostasis, in order to stay in homeostasis you need to excrete all the sodium that comes in. In other words sodium in equals sodium out.
However these patients are not in water balance. they have a disease that forces their ADH to 11. They have a fixed ADH secretion and it is set at full blast. This minimizes urinary water excretion, but they are able to stay in sodium balance. So the net of this is they make only a little bit of urine but that small amount of urine carries all of their ingested sodium (sodium in = sodium out) so the sodium is excreted in a small volume at a high concentration.
Now the obvious problem here is that they are holding on to an excess of water. And that will increase their total body volume. This is subtle and doesn’t cause edema, or heart failure, or fluid overload in the lungs, but it is there. This fluid overload suppresses angiotensin 2 and decrease sodium resorption in the proximal tubule and hence decreases urea (and uric acid in our model) reabsorption.
And yes this does mean it is not exactly sodium in = sodium out, there will be a slight excess of sodium excretion.
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OUWB Question: Acid-Base

Hi Dr. Topf,
(I don’t have Twitter) I wanted to ask you about question 6 on the week 2 quiz:
“An unresponsive woman is brought to the emergency room. She has a history of a suicide attempt a few years earlier. The lab tests are: Serum Na 140 mmol/L Serum K 4.0 mmol/L Serum Cl 100 mmol/L Serum HCO3 14 mmol/L, BUN 17 mg/dl, creatinine 0.7 mg/dL, serum osmolality 323 mOsm/Kg, Blood glucose 72 mg/dl, Blood gases: pH 7.28 pCO2 27 mmHg. What would you expect the urine pH to be in this patient?”
Why is it that we would expect the urine pH to be acidic? Since blood pH is 7.28, I would imagine that urinating out HCO3- (explaining the low serum HCO3) would have caused the acidic blood pH, thus making urine pH basic?

 

Thanks for your help,

When answering multiple choice board-style question try to figure out what they are looking for. Let’s break this down.
“An unresponsive woman is brought to the emergency room. She has a history of a suicide attempt a few years earlier.

This is the “tell” of the stem. Acid base + suicide = ethylene glycol toxicity

The lab tests are: Serum Na 140 mmol/L Serum K 4.0 mmol/L Serum Cl 100 mmol/L Serum HCO3 14 mmol/L, BUN 17 mg/dl, creatinine 0.7 mg/dL , Blood glucose 72 mg/dl, 

They don’t tell you the anion gap. Calculate it.

Anion gap = Na – (Cl + HCO3)
Anion gap = 140 – (100+14)
Anion gap = 26 (normal 6-12)

High anion gap.

serum osmolality 323 mOsm/Kg

More of the tell. They won’t tell you the osmolality unless they want you to calculate the osmolar gap (or it is a hyponatremia question)

Osmolar gap= Measured osmolality – (Na x2 + glucose/18 + BUN/2.8 + ethanol/3.6)
Osmolar gap = 323 – (280 + 4 + 6 + 0)

Osmolar gap = 323 – 290
Osmolar gap is a massive 33 (Upper limit of normal is 10, over 20 starts to gain a lot specificity for toxic alcohol)
This confirms our earlier suspicions of ethylene glycol toxicity

Blood gases: pH 7.28 pCO2 27 mmHg. What would you expect the urine pH to be in this patient?”

The ABG confirms the metabolic acidosis.

Let’s do Winters formula (not really needed for this question, but you know…practice)
1.5 x 14 =21 + 8 =29, measured CO2 is within ±2 of predicted so an appropriately compensated metabolic acidosis.

Why is it that we would expect the urine pH to be acidic? Since blood pH is 7.28, I would imagine that urinating out HCO3- (explaining the low serum HCO3) would have caused the acidic blood pH, thus making urine pH basic?

So the bicarbonaturia you are talking about would happen if the cause of the metabolic acidosis is renal loss of bicarbonate (what we call renal tubular acidosis).

RTA should only be considered if you are dealing with an normal (or non-anion gap) metabolic acidosis. Since we have an anion gap metabolic acidosis and functioning kidneys the kidneys will be working as hard as possible to clear the exogenous acid. This means the urine is acidic.

The urine would also be acidic if the patient had a non-anion gap metabolic acidosis from diarrhea.

Hope this helps

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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 tubulo-glomerular 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 the filtered fluid you could very rapidly 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.

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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…
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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. ❞

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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:

higher quality export pic.twitter.com/uNIBmEAn7c

— Joel Topf, MD FACP (@kidney_boy) July 14, 2017

Pre-ESRD Depression and Post-ESRD Mortality in Patients with Advanced CKD Transitioning to Dialysis @kamyarkalantarz https://t.co/z4wYW99SEb pic.twitter.com/46J4acS3sa

— CJASN (@CJASN) July 5, 2017

Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders https://t.co/6m1JCKrqdS pic.twitter.com/Z3PiWJ0NqU

— Hector Madariaga, MD (@HecmagsMD) July 20, 2017

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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.

Nine.

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.