Tag: clearance

Posted on

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
Posted on

Fellow-level lecture on urea kinetics

I reworked an old lecture from ’05 on urea kinetics. The old lecture had a hideous purple background, so changing that to black would have been enough but I added a number of cool touches to fully update it. It worked pretty well, though the end’s pacing is off.

PowerPoint | PDF

I especially like the sequence walking through using the iPhone to calculate the simplified single pool Kt/V. Its amazing how many people don’t realize that turning the calculator sideways brings up scientific functions. I love watching their faces light up when I say, “Now turn it sideways.”

The lecture uses the three randomized controlled trials on dialysis to introduce and explain the three varieties of Kt/V:
  1. NCDS: to discuss single pool Kt/V
  2. HEMO: to discuss equilibrated Kt/V
  3. Frequent Hemodialysis Network in center study: to discuss standard Kt/V
I have another hour long time slot in December to talk about dialysis prescription. I’m going to discuss the recent data on dialysis interval and mortality. 
What else should I talk about?

Posted on

Creatinine, BUN and GFR: part two

Part one focussed on the fact that with a stable creatinine the amount of creatinine produced is equivalent to the amount of creatinine excreted in the urine. Then it showed how the general clearance formula can be rearranged to solve for the serum creatinine rather than the GFR.

The interesting concept, and the original question, is why does the creatinine rise when the GFR falls. Looking at the clearance formula if we decrease the GFR to 45 mL/min and keep the creatinine excretion fixed at 1,400 mg per day, the only way to balance the equation is to increase the serum creatinine.

In summary we have an equation with three variables:
  1. Clearance is the independent variable, and we are setting it at 45 ml/min
  2. Creatinine excreted is fixed at 70 mg/kg or 1,400 mg
  3. Serum creatinine
So if the GFR falls the only variable that can respond is the serum creatinine and in the above example it rises to 2.1 (remember to multiply the calculation by 100 to convert from mg/ml to mg/dL).

The only way for the kidney to excrete the daily creatinine load is to allow the creatinine to rise. The increase in serum creatinine allows the kidney to clear the daily creatinine load.

But this doesn’t really answer why the creatinine rises with a falling GFR. The secret comes from the efficiency of ultrafiltration as the source of clearance. Excluding secretion in other parts of the nephron clearance is provided by filtration at the glomerulus.

Substances filtered at the glomerulus are found in the ultrafiltrate at the same concentrations they are found in the plasma. So a liter of ultrafiltrate will have 140 mEq of sodium and 4 mEq of potassium. These examples should make it clear that ultrafiltration is much more efficient for excreting substances found at high concentration. Americans consume about 180 mmol of sodium a day (4140 mg), this can be cleared with less than 1.5 liters of ultrafiltration. Potassium intake is around 50 mmol per day, clearing this much potassium requires 12 liters of ultrafiltrate. Note: sodium and potassium handling do not depend on ultrafiltration because of extensive reabsorption and secretion that largely overwhelm the effect of ultrafiltration.

Let’s look at the patient at steady state with, 1,400 mg of creatinine production, a GFR of 100 and a creatinine of 0.97. He suddenly loses half his renal function and now has a GFR of only 50 mL/min. Looking at the clearance formula, the only things that changes at first is the GFR. For the first moments after the loss of GFR the serum Cr will still be 0.97. We can solve for amount of creatinine excreted by the kidney at the GFR:

So with a GFR of 50 and a serum creatinine of 0.97, only 698mg, or just under half, of the creatinine created is excreted by the kidneys. It is impossible for the kidneys to clear the daily creatinine load with a GFR of 50 and a serum Cr of 0.97. The 702 mg of creatinine that are not excreted, remain behind and serves to increase the serum the creatinine. If the patient has 60% body water, his total body creatinine initially was 407 mg of creatinine (0.97 mg/dl x 420 dL body water) and the additional retained creatinine will raise his serum creatinine to 2.6 (407mg + 702mg divided by the same 420 dL).

The next day, armed with the higher serum creatinine of 2.6, the same GFR allows the body excrete 1,929 mg of creatinine, more than the daily creatinine load. The resulting creatinine is then 1.4 mg/dl. Ultimately if you carry this calculation forward the creatinine will stabilize at 2.16 mg/dl.

Understanding the equations and calculations is not as important as understanding that higher serum creatinines allow more creatinine to be cleared by ultrafiltration, in fact the only way for the kidney to excrete the same daily creatinine load at lower GFRs is by allowing the serum creatinine to rise.

Think of a rising creatinine as not so much a complication of renal failure but as an adaptation to renal failure.

Posted on

Creatinine, BUN and GFR: part one

Question: What is the most basic concept in clinical nephrology?

Answer: As renal function falls, the creatinine and BUN rise.

For the purpose of this post the renal function is synonymous with glomerular filtration rate.

Think about every lab measurment in clinical medicine and think about how the normal range changes as the GFR falls from 100 mL/min to 10 mL/min, a 90% reduction of renal function.

  • How much does sodium change? 
    • Not at all.
  • How much does potassium change? 
    • In the absence of ACEi or other drugs which alter normal renal handling or an extreme change in diet, it doesn’t change at all.
  • Phosphorous? 
    • Maybe a 25% bump from the low 4s to the mid 5s.
  • White blood cell count? 
    • Not at all.
  • Albumin? 
    • Not at all.
  • Lipase? 
    • Not at all.
  • SGPT? 
    • Not at all.
In the broad world of clinically relevant biochemical tests, essentially none are readily affected by changes in glomerular filtration rate. BUN and creatinine (and cystatin C) stand alone in their exquisite sensitivity to changes in GFR. Of course this is not a weird coincidence, those labs are clincially relevent precisely due to their sensitivity to changes in GFR. But why is it, that as GFR falls, the creatinine rises?
Imagine a 70 kg male. Men, on average, generate 20 mg of creatinine per Kg body weight, so our patient will generate 1400 mg of creatinine and, if the renal function is stable, all of that creatinine is excreted by the kidneys every day. It makes no difference if the GFR is 10 or the GFR is 100, all of the creatinine generated is excreted.

None of it lingers.

None of it accumulates in some creatinine depot in the subcutaneous fat or lateral horn of the cerebral ventricles.

This has to be true because if some of creatinine hung around and accumulated, the serum creatinine would rise. By definition, stable renal function means the creatinine doesn’t rise. So our 70 kg man generates 1,400 mg of creatinine and excretes 1,400 mg of creatinine.

Once you know the amount of a substance excreted we cane solve for the plasma concentration using the standard clearance formula.
Using the 1,400 mg of creatinine, assuming a modest urine output of 1 liter and assuming a GFR of 100 the equation looks like this:
We can rearrange the equation to solve for the plasma creatinine:
and if you do the calculation you get a creatinine of 0.97 mg/dL. The neat part of the equation is that it is totally independent of the urine volume. If the patient excretes the 1400 mg of creatinine in 2 liters rather than 1 as we claculated above, the urine creatinine concentration falls by half (same amount of total creatine dissolved in twice as much urine), the urine volume doubles and the serum creatinine remains the same.
On the other end of the renal function spectrum, the poor patient with a GFR of 10, looks like this:
This gives him a serum creatinine of 9.7 mg/dL. The creatinine went from 0.97 to 9.7 with a change in GFR from 100 to 10. Imagine if any other electrolyte had a ten-fold change associated with a drop in the GFR? Raise your hand if you have seen a potassium of 40.

President Bush is 5’11”

You can use this spreadsheet below to predict the serum creatinine based on different GFRs, urine volumes and creatinine production. Try different urine volumes and see how that doesn’t affect the serum creatinine (the reason is that the numerator in the clearance formula is simply solving for the mass of creatinine excreted. Concentration of X multiplied by the volume gives amount of X dissolved in the solution.) . Use the spreadsheet to discover what Shaquile O’Neal’s serum creatinine is. Assume 20 mg/kg body weight, a weight of 147 kg, and a GFR of 120.

If you want to edit and use the equation image files download this Word file. Double click the equations to launch the equation editor.