Monday, February 28, 2011

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.
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