Author: Joel Topf

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New Tweetorial: Comparing diffusive versus convective clearance

I have been workshopping this one for awhile in my mind and today I carved out a few hours to create it.

It starts here

Part of the inspiration for this came from an epic message on the Channel Your Enthusiasm back channel by Roger Rodby

Here is the draft of the script.

Diffusive vs Convective clearance

I was teaching the third year medical students about acute kidney injury and the lecture begins with a brief history of extracorporeal dialysis for AKI. And I asked a student what extracorporeal dialysis was, and he correctly identified it as “dialysis outside the body.”

Since the ironclad law of the Socratic Method is that every correct answer is rewarded with another, harder, question, I replied, “Can you think of any example of intracorporeal dialysis?” The right answer is peritoneal dialysis, but he said , “The kidney?”

And off on a tangent we went…
Does the kidney even do dialysis? No. The kidney does not use diffusion to clean the blood. Clearance is provided by convection at the glomerulus. Plasma is squeezed through the slit diaphragms of the podocytes in the glomerulus but besides the lack of protein, the solute composition on both sides of that membrane is essentially identical.

The kidney does not clear the blood by diffusion, the defining characteristic of dialysis, but rather by convection. How does that work? Glad you asked. Take Creatinine. The creatinine on both sides of the podocyte is the same, 4.4 mg/dL in this example.

4.4 mg per dL x a GFR of 25 mL per minute x 1440 minutes in a day divided my 100 mL in a dL comes to 1584 mg of creatinine filtered.

That is just about the amount of creatinine produced by a typical person a day. 

So convective clearance can clear all of the creatinine produced everyday, the additional creatinine secreted in the proximal tubule is just gravy. 

What about sodium? 

138 mEq/L x a GFR of 25 mL per minute x 1440 minutes in a day divided by 1000 mL in a L comes to 4968 mE of creatinine filtered. 

This is a problem since we only consume around 100-200 mEq of sodium a day. So this where the tubules earn their stripes by reabsorbing all the excess filtered sodium to keep us from peeing ourselves to death.

So these two examples demonstrate an important principle of convective clearance, it is better for clearing things at a high concentration than at a low concentration. In fact, a GFR of 1 is enough to clear a typical sodium daily load.

138 x 1 ml/min x 1440 min/day divided by 1000 ml/L = 198 mEq/day

This why even a tiny residual renal function makes a huge difference in dialysis patients. 

But that same GFR of 1 would only clear 

4.4 x 1 ml/min x 1440 divided by 100 ml/dL = 63 mg of creatinine only about 4% of the daily creatinine load.*

*This calculation is highly dependant on the serum Cr concentration, which would be a lot higher than 4.4 if the GFR was 1, but since a GFR of 1 in incompatible with life, the patient would also be getting renal replacement therapy, so it is hard to know where the serum Cr would actually be.

So after explaining that the kidney didn’t actually do dialysis, or anything remotely close to dialysis. I asked if there was an organ that did do dialysis? Or, more specifrically, used diffusion for clearance.
Answers from the crowd: 

Liver > nope

Spleen > nope

Skin > nope

And finally, Lung? Yup.

The lung clears carbon dioxide from the body and absorbs oxygen by setting up a setting where the gasses move down their respective concentration gradients across a semipermeable membrane. You know, like dialysis.

A ventilator is not really like an artificial lung, in the way a dialysis machine replaces the core function of a kidney. It provides flow, but no clearance. We still are dependent on the alveolar membrane for oxygen absorption and carbon dioxide clearance. 

But ECMO is an artificial lung and fully replaces the alveoli and uses the principles of dialysis to clear carbon dioxide and move oxygen into the blood. So at some level, ECMO is closer to the lung than dialysis is to the kidney. 

One final note on this thread is in regards to dialysis and convection. The kidneys work by convective clearance but our primary means of replacing them is by diffusive clearance. However this summer we saw a randomized controlled trial of modifying dialysis to use convection rather than diffusion…and the result? Significant reduction in total mortality. 

We don’t get a lot of wins in dialysis, so when we get one, we pay attention.

The script isn’t exact because I have to do some edits to meet the character limits of tweets.

Here are the Keynote slides that I used to create the gifs.

Diffusion v Convection
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Is the juice worth the squeeze?

I have a long-time patient who came in yesterday and we were reviewing their labs together and noted a tremendous success. The patient’s albuminuria has fallen 90% since 2018. This is due to adding and then maximizing losartan, adding dapagliflozin, and most recently starting finerenone.

Here is the albuminuria over time:

Over that time their eGFR looks like this:

How should we square the recent drop in eGFR with the reduction proteinuria? We typically switch to a risk based model, here are their Tangri KFRE scores over time:

I was quite surprised to see the KFRE rise over time despite the 90% reduction in albuminuria. I am not changing therapy. The eGFR is nearly intact and I am not going to tiny changes in creatinine (the most recent jump was less than 0.2 mg/dL) guide therapy decisions. I am going to continue to ride these medications which have repeatedly been shown to protect kidneys (and hearts).

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OUWB Question: What’s going on with this mess?

I create all of my presentations in Keynote. In the past I was able to present them in Keynote but due to construction and having to give lectures in 156 of North Foundation I had to convert the presentations to PowerPoint. And then hope that PowerPoint on the PC was mostly like PowerPoint on the one true computer, the Mac. It works surprisingly well, but this slide is an outlier.

Here is what it looks like in PowerPoint on my iMac

This is better, but how does this slide fit into the lecture? It is a summary slide after I have discussed two of the causes of the maintenance of metabolic alkalosis. Here is the slide that introduces the four mechanisms for maintaining metabolic alkalosis

Then the lecture describes kidney failure (the easiest to unsderstand)

After that I cover the mechanisms by which hypokalemia maintains metabolic alkalosis in 7 slides as seen here:

The I do the same for chloride (volume) deficiency in 7 slides:

After going through that I noted similarities between the mechanisms of hypokalemia and chloride deficiency, the summary slide is designed to highlight those. Looking at that slide now, it doesn’t do such a good job of that. Does this pair of slides work better?

Here is the revised powerpoint for you to download

Metabolic Alkalosis 2023
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You cannot tell if a respiratory acid-base disorder from the ABG

This is a frequent cause of confusion. I know that I was confused by this when I was a young learner. And I believe the source of this confusion was garbled teaching from a resident that was still struggling with the concept.

Take this ABG:

pH: 7.26

PaCO2: 80

HCO3:
39

The Henderson-Hasselbalch variables are moving in discordant directions (pH down, pCO2 and HCO3 going up) so it is a respiratory disorder. The pH is decreased so this is a respiratory acidosis.

Now look at the compensation to see if there is a second primary disorder affecting compensation.

  • In acute respiratory acidosis the HCO3 rises 1 mEq/L for every 10 mmHg the CO2 rises.
  • In chronic respiratory acidosis the HCO3 rises 3 mEq/L for every 10 mmHg the CO2 rises.

This patient’s CO2 is 80, an increase of 40, so the HCO3 should rise 4 (4×1) if the respiratory acidosis is acute, yielding a bicarb of 28 (24+4). The actual bicarbonate is 39, too high, so there is an additional metabolic alkalosis if the respiratory acidosis is acute.

If the respiratory acidosis is chronic, to increase in CO2 of 40 should increase the bicarbonate by 12 (4×3), so a bicarb of 36 (24+12). The actual bicarbonate is 39, which is just outside of our ±2 so we’ll call it nearly appropriate with just a touch of metabolic acidosis.

The ABG can be “solved” with either acute or chronic respiratory acidosis. Patients cannot be diagnosed with Occam’s razor so the simpler explanation (chronic respiratory acidosis without the need for additional acid-base disorders) may not be the right one. In medicine we need to assume Hickam’s Dictum “A patient can have as many diseases as he damn well pleases.”

The ABG does not determine whether a patient has acute or chronic respiratory disorder, the physician must do that.

So what’s my beef with the two Bruces? Take a look at this question from chapter 8…

The simple acid-base disorders are:

  1. Metabolic acidosis
  2. Metabolic alkalosis
  3. Respiratory acidosis
  4. Respiratory alkalosis
  5. Respiratory acidosis
  6. Respiratory alkalosis

But this is answers the authors expect…

Since the question stipulates that these are simple acid-base disorders, one can extrapolate the acuity of the respiratory disorder by the degree the bicarb has adjusted, a large adjustment is chronic, and a smaller change is acute. But since patients don’t tell you if they have simple or complex acid-base disorders when the blood is drawn, this trains students to expect the ABG to provide information that it cannot provide.

Stupid book.

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OUWB student question on ammonium production and potassium

How does hyperkalemia or even alkalosis suppress NH3 production?

So the mechanism is not completely worked out but the conventional explanation is…

Hypokalemia causes potassium to shift out of the cells. Hydrogen ions then move on the opposite direction into cells to maintain electroneutrality.

This causes intracellular acidosis. The intracellular acidosis causes the cells of the proximal tubule to erroneously concludes that there is systemic acidosis and so they up regfulate the production of NH4 to increase renal excretion of acid and produce new bicarbonate.

An interesting note about this happens in liver failure. Patients with liver failure are unable to metabolize ammonia and levels build up to high concentrations and can cause hepatic encephalopathy. A known risk factor for this is hypokalemia. The above paragraph provides an explanation for this.

Conclusion from a recent study on this phenomena (Ref)

Hyperkalemia works the same way but in reverse. Potassium shifts into the cells, This causes hydrogen to move out of the cells and causes intracellular alkalosis. The cell mistakes this intracellular alkalosis for systemic alkalosis and the last thing the kidney wants to do in systemic alkalosis is generate additional bicarb, so it down regulates this generation of ammonium.

Slide 97 from Monday’s lecture
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OUWB: So you’re lost in renal and looking for a map

If you are a reader and need a book to help you understand renal physiology, may I suggest:

Renal Physiology by the Bruces (Koeppen and Stanton) Amazon

It is well written and is targeted at pre-clinical medical students. We are using it for our fellow renal physiology class and I don’t love it for that (no references for one).

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OUWB: Podcasts of interest

If you are taking the M2 renal class and are looking for a way to study while cleaning, exercising, walking the dog, or commuting, allow me to suggest a few podcasts that may be of interest.

Curbsiders Podcast on rapid interpretation of ABGs

Curbsiders #104: Renal Tubular Acidosis

The Curbsiders: Hyponatremia

Curbsiders: Hypernatremia

Hyperkalemia with The Curbsiders

Channel your Enthusiasm This is an award winning podcast podcast series on renal physiology. The intended audience is nephrology fellows and clinicians so it may aim too high, but if you like podcasts and a group of experts getting together to geek out on a topic they love it may tickle your fancy.

A long list of interesting podcasts for interested medical student