The issue of whether a marked elevation in the BUN when compared with the creatinine might represent gastrointestinal bleeding was nicely covered previously on RFN. One of our attendings recently had our group of first year fellows review the issue using a quantitative approach that highlighting the relevant physiology.
Consider a 72kg male in steady state eating 90grams of protein per day with a creatinine clearance of 120ml/min and a Urea clearance of 60ml/min.
Remembering that a male will produce about 20mg/kg of creatinine a day, our 72kg male will produce 1440mg of creatinine in a day…
72kg x 20mg/kg = 1440mg
A person in steady state must excrete what they produce (a key nephrology concept). So if our man makes 1440mg of creatinine he must excrete 1440mg of creatinine (if he fails to excrete it all his plasma creatinine concentration will rise and he has fallen out of steady state).
We can additionally estimate the amount of BUN produced by remembering that urea nitrogen production is approximately 1/6th of protein intake. So our man eating 90grams of protein produces 15grams of urea nitrogen each day (90grams x 1/6 = 15grams) which in steady will be excreted.
With the above we can now calculate the plasma creatinine and BUN concentrations using the clearance equation…
clearance (C) = [urine concentration (U) x urine volume (V)] / plasma concentration (P)
C = UV/P
Plug in the numbers correcting the units along the way for Cr…
120ml/min = (1440mg/day) / P
P = (1440mg/day) / 120ml/min
P = (1440mg/day) / 172,800ml/day
P = 0.0083mg/ml
P = 0.83 mg/dl
Same deal for BUN…
60ml/min = (15g/day) / P
P = (15g/day) / 60ml/min
P = (15,000mg/day) / 86,400ml/day
P = 0.17mg/ml
P = 17 mg/dl
A final thing we can sort out from what was provided is the fractional excretion of urea which by convention is expressed in percent. This is just what it says it is, the fraction of filtered urea (we'll approximate GFR with CrCl) that gets excreted in the urine. As urea is freely filtered this is…
FeUr = (Urea clearance / GFR) * 100
FeUr = (Urea clearance / CrCl) * 100
FeUr = [(60 ml/min) / (120 ml/min)] * 100
FeUr = 50%
So here’s what we know in table form…
Now imagine that our man starts feeling unwell, stops eating and has a one liter bleed from a peptic ulcer into his GI tract. For arguments sake lets say this occurs with no drop GFR (the “it’s the blood not the renal function” argument).
His protein intake is now the protein content of 1L of blood. 40% is cells (mostly rbcs) and 60% is plasma. The major proteins in the cellular and plasma parts respectively are hemoglobin and albumin (there's a bit more protein around from globulins and so on but this will give us a rough estimate).
Normal hemoglobin and albumin concentrations would be 14 g/dl and 4 g/dl respectively. So from the above we can estimate the protein content of blood in the GI tract…
1L * 0.60 = plasma volume
0.6L = plasma volume
plasma volume * protein concentration = plasma protein content
0.6L * 4g/dl = plasma protein content
0.6L * 40g/L = plasma protein content
24g = plasma protein content
1L * 0.40 = cellular volume
0.4L = cellular volume
cellular volume * protein concentration = cellular protein content
0.4L * 14g/dl = cellular protein content
0.4L * 140g/L = cellular protein content
56g = cellular protein content
Total protein content = cellular protein content + plasma protein content
Total protein content = 24g + 56g
Total protein content = 80g
Using our previous calculations our table now looks like this…
Notice that in the above scenario the BUN drops a bit as the protein intake has decreased. What if we kept our man eating the same diet and had him bleed at the same time while holding kidney function stable?
If you almost double the protein intake you almost double the BUN (from 17 to 33 mg/dl). Now let’s try the stopped eating, 1 liter bleed scenario along with a 50% drop in GFR due to hypotension. Remember that in the volume depleted state the fractional excretion on urea is typically less than 35% and for arguments sake we’ll make it 20% in our man.
As compared with no renal dysfunction we now get an BUN/Cr ratio of 23 as compared to 18. How about we run scenario with continued eating, 1 liter bleed and now with 50% drop in GFR due to hypotension with the associated drop in urea clearance.
Pretty impressive, huh? With a bit of kidney dysfunction added into increased urea production we’ve now got a BUN/Cr ratio of 98 vs 40.
The point of all this is that the BUN and serum creatinine will vary based on:
1) Cr production
2) Cr clearance
3) BUN production
4) BUN clearance
The integration of these four things yields the BUN and serum creatinine values and the subsequent ratio between the two.
As noted by Ernest, the dog paper he reviewed and the math above the most impressive BUN/Cr ratio elevations are generated by a combination of increased urea nitrogen production and decreased urea clearance. The ratio is further accentuated by the proportionally greater drop in urea clearance vs creatinine clearance seen in volume depletion.