What is missing from the race and eGFR discussion

The ASN and NKF have a joint task force working toward a response to the race and eGFR problem and they are now inviting people to submit oral and written testimony. I signed up. Hopefully I get an opportunity, but suspect there will be too many people for them to hear even a fraction of the applicants.

I have been thinking about race and eGFR and this is where I am at…

  • Race is a social not a biological construct
  • People identified as black (or self-identified as black) have higher measured GFR for the same serum creatinine as non-blacks
  • These higher eGFR results in black people (self-identified or not), a marginalized group and a population already at increased risk of adverse kidney outcomes, being denied transplant listing and CKD referral.

But what is not ever seem to be questioned in this discussion is the perverse use of estimated GFRs to make critical binary decisions in individual patients. The eGFR equations are amazing how well they predict GFR for groups of patients with minimal bias, but their reliability in an individual is stunningly imprecise. Accuracy in individual patients is measured by P30, the likelihood that the true value will be within 30% of the measured value. The P30 is 84% with CKD-Epi, a bit better compared to the 80% in MDRD. This means that for the critical decision of whether to list a patient for a kidney transplant, a patient with an eGFR of 21 will have an actual measured GFR somewhere between 15 and 27 in 84% of cases. This 30% spread is greater than the 16% adjustment for black race.

Though using race for eGFR should be stopped, and we can do that today by making cystatin-c the coin of the realm, this doesn’t change the problem of over indexing on eGFR for individual patient decisions. Cystatin C is no better than creatinine in providing a precise estimate in eGFR (P30 86%). Decisions like transplant listing and CKD referral should not rely on a measurement with so much uncertainty. We report eGFR on lab reports but give physicians no sense of the imprecision hidden in that number.

I think if eGFR were reported as a range (±30%), we would stop using sharp cut-off limits for critical decisions like transplant and referral.

The use of sharp cutoff for decisions like transplant and CKD referral harms all patients with CKD, not just black people. We should immediately to remove race from eGFR calculations by standardizing cystatin-C as the way to assess eGFR but at the same time we should start the process of unwinding guidelines and individual patient decisions from being wedded to inaccurate estimates of GFR.

A couple of new Tweetorials

The first was in response to Robert Centor’s excellent description of how he uses reciprocal creatinine. Honestly I had not thought about reciprocal creatinine in a long time. It was fun diving into some of the literature around it. Here is the tweetorial:

Today I did a second tweetorial on hyperosmotic hyponatremia

Here I had some technical problems. I wrote the entire tweetorial using chained tweets in Safari on MacOS. When I went to upload all tweets, Twitter hung and failed to upload more than the first 8. I had to then go through and re-post the remainder of the tweetorial. I was frustrated and failed to attach two of the animated gifs I made. I added them as additional tweets but they break the flow. Tweetorials are like writing email newsletters, once you publish the tweets (or hit send on the newsletter) there is no opportunity for editing.

Is estimated GFR racist?

Update from January 2021: This is an old post and I have evolved my thoughts on this issue. I leave this here mainly as bread crumb on the trail of my evolving thoughts about this topic.

 

 

Zachery Berger published this epic tweet storm last week about estimated GFR. It starts here:

The conclusion is that using race in the MDRD formula (and by extension the  CKD-epi formula) is inherently racist.

I do not think this is the case. Trying to estimate GFR from a serum creatinine and a few demographic variables is impossible, the best we can hope for is a reasonable guess. To see how bad we are take a look at the wide variability at high GFRs with the current CKD-Epi formula:

So that GFR of 60 has a 95% CI of being between 35 ml/min and 92 ml/min. Not so reassuring.

One of the primary reasons for this imprecision is that creatinine production varies from body to body. When one person produces more creatinine than another, for a set rate of creatinine excretion his serum creatinine concentration (what we measure on a blood test) will be higher. Who produces more creatinine? People with more muscle mass.

  • Larger people produce more creatinine than smaller people
  • More muscular people produce more creatinine than less muscular people
  • People with four limbs produce more creatinine than people with 3 limbs
  • Men produce more creatinine than women, on average
  • Young people produce more creatinine than older people, on average
  • Vegetarian Indians produce less creatinine than westerners
  • Black people produce more creatinine than non-black people, on average

The data is shown in figure 1 of Levey’s 1999 study.

Even though Dr. Berger did not draw the conclusion that estimated GFR is inherently sexist, let’s look at gender first. I have recolored the two graphs and superimposed them on one another. Men are in red and women are in blue:

It is clear that for any given GFR the men tend to have a higher creatinine than the women. This is not perfect and it is not hard to pick out individuals where this generalization fails, but in general this is a fair generalization. Levey comments and quantifies this gender difference:

At any given GFR, the serum creatinine concentration is significantly higher in men than in women (P 0.001).

The figure, without any recoloring, provides the curves for black (solid line) compared to non-black (dotted line) patients. Again it is clear that the average GFR is higher for black patients at any set creatinine. Levey comments and quantifies the racial difference:

At any given GFR, the serum creatinine concentration is significantly higher in men than in women and in black persons than in white persons (P=0.001).

Dr. Berger misses this fact:

How do we know *that* to be true? BECAUSE THEY MEASURED IT!

The refernces are just there to show that this is not a new and novel finding. This was an expected finding. The study does not rest on these references. The investigators in the MDRD study measured the serum creatinine, GFR, and asked patents if they were white, black or hispanic. The data shows that black people had, on average, 18% higher GFR for any measured creatinine. The fact that the prior work on this subject was deplorable does not alter the findings.

Berger is so upset that the estimated GFR differentiates black and white people that he misses the real problem with the MDRD study, the embarrassing lack of black people in the original data set. Only 12% of that cohort was African American, less than 200 people. A group that has the greatest incidence of end-stage kidney disease should be over-represented in a study about reducing the progression of CKD, not under-represented. Remember, Levey was using the data already collected for the Modification of Diet on Renal Disease study. This was not de novo data collected for the purpose of generating this equation. This weakness was corrected in the CKD-Epi equation where there were nearly 3,000 African Americans representing 30% of the cohort. The adjustment for race went from an 18% bump in GFR for a given creatinine down to 15.9%. Not much difference.

We use race, gender, and age not because we are racists, sexists, and agists, but rather because there are physiologic differnces between the races, the genders, and the aged. We exploit those differences to improve the accuracy of our estimate. All of these adjustment are just attempts to use demographic variables to squeeze a better correlation of GFR from a serum creatinine.

When the GFR is zero how fast does the creatinine rise?

 

How do you get a GFR of zero?
Bilateral bathtub nephrectomy
NephrO-kleptO-mainia

In my clinical experience as the GFR approaches zero the creatinine goes up between 1 and 2 mg/dL everyday.

However I was working out a story problem for an acute renal failure and when I calculated how much the creatinine would rise it was 3.3 per day. Here is how I calculated this:

  • Total body creatinine: 420 mg
    • This assumes that creatinine is equally distributed through out total body water. So 42 liters (60% of 70kg) times 1 mg/dl times 10 dL per liter
  • New creatinine: 1400 mg
    • 20 mg of creatinine generation per kg body weight, 70 kg body weight
  • New total total body creatinine 1820 mg
    • add the first two figures
  • New creatinine: 4.33 mg/dL
    • Divide the total body creatinine (1820 mg) by total body water (420 dL):

Did I do my calculation wrong? The total body creatinine calculation of 420 mg seems awfully low, especially if muscles create 1400 mg of new creatinine everyday.

Picture by The Doctr

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.

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.

Over collection or just a big guy


A patient came to my office with a creatinine of 2.2 indicating a GFR of 33mL/min by the MDRD formula. 

His primary care doctor ordered a 24 hour urine for creatinine and protein as part of her work-up for CKD:
  • 24-hour urine creatinine was 3,232 mg 
  • 24-hour urine protein was below the level of detection (<183>
To calculate the CrCl multiply the urine cr (total mass, not the concentration) by 100 then divide the product by 1440 (the number of minutes in 24-hours) and then by the serum creatinine (in mg/dl).
  • His CrCl is 102 mL/min
This is a huge discrepancy: 
  • Advanced Stage 3b CKD by MDRD
  • Normal kidney function by 24-hour urine collection
The first thing you should do is determine if the 24-hour urine was an adequate sample. Usually I worry about under-collections of urine due to a missed void or spillage. In this case I worried that an over-collection was masking renal failure.  (i.e. Did he collect his urine for more than 24-hours? Did his wife join in and contribute to the collection?) The average man produces 23 mg/kg of creatinine. The average woman produces 18 mg/kg. I am unaware of the proper figures for children.
His body weight is 123 kg and the 24-hour creatinine collection was 3,232 mg. This yields 23 mg/kg, right on the money for an average adult male.
This is just a big guy and this is where the MDRD can fail us.
Supporting the diagnosis of CKD stage zero was a normal renal ultrasound, a lock of proteinuria and a normal U/A and microscopic exam.

Teaching on Two Ell: Acute Renal Failure and GFR

Yesterday we discussed the problem with the curvilinear relationship between gfr and creatinine and how the MDRD equation dispenses with this problem. Today we will go over a handout introducing GFR, MDRD and how to manage them, including referral to a nephrologist.

Additionally I want to do my canned acute renal failure lecture. This lecture has been made obsolete by the recent ATN data and data from Vanderbilt so it will need to be revised.

ARF No ATN Data

View SlideShare presentation or Upload your own. (tags: arf atn)