Friday, 25 April 2008

What is creatinine clearance?

Let's approach the answer to this question in stages. I've chosen to work from first principles here, but if you get bored, never fear. You can safely skip from wherever you get up to until the nice pretty equation near the end!

The kidneys filter a truly enormous amount of blood each day (see below!). However, things like diabetes and hypertension can damage and destroy them, and so it's important to know how they are doing. How do we tell?

We can't very well look at the kidneys, since they're obviously hidden from sight. We could, I suppose, perform either surgery or a biopsy in order to bring a piece of kidney to us, but this seems a little extreme, to put it mildly.

No, let's rather try a more indirect method. The kidney is supposed to do certain jobs, so what if we checked on the outcomes of these jobs to see if the kidney was doing them adequately. This is analogous to me seeing if you're packing enough of my boxes by, rather than watching you, merely counting the number of boxes packed at the end of the day. A little indirect, granted, but it avoids the bloodshed of the biopsy option.

Great all, set then. We could choose urea, say, or creatinine - two things normally excreted by the kidney. We could measure their blood concentrations, and if these measurements were normal, we could presume that the kidneys were doing OK. On the other hand, elevated levels of either urea or creatinine would suggest to us that the kidneys weren't excreting enough of them (although we would have to exclude other causes).

But there's a snag. The kidneys are massively redundant - that is, they have lots of reserve. In fact, you have to kill off more than 50% of the glomeruli before the levels of things like urea and creatinine will rise at all. This is why it's reasonably safe (but not a good idea, all things being equal) to donate one kidney to someone else. Although this redundancy is a good idea overall, it does rather bugger up our plan. This is because urea and creatinine (and anything similar) will only start to change in their blood concentrations once more than 50% of the kidneys are destroyed. So our original idea only tells us something is wrong with the kidneys once something is very wrong, which might be too late.

Hmm - what we really need to be asking is how much blood is being filtered per minute, isn't it? This is much more sensitive as far as damage detection goes, since if you lob off 10% of the kidneys, the amount of filtrate per minute must go down accordingly, even if the remaining 90% of the kidneys are able to take up the slack with regards to urea and creatinine.

Ok, but how do we measure this glomerular filtration rate then? Once again, let's start with a few instructive mistakes and work our way forwards.

If the kidney did no reabsorption at all, calculating the rate of filtration would be easy - we could just collect all the urine formed in a certain amount of time. For instance, if I produced 60 ml of urine in an hour, I could say that my filtration rate was 1 ml/min.

But, alas for us, the kidney reabsorbs more than 99% of what it filters. Together they filter a staggering 180 litres per day, and this allows for the biggest possible chance at excreting unwanted things. However, it is clear that you can't simply excrete this amount - or we would all be drinking the whole day long, having to take in the 180L that we're excreting. We would also have to do this drinking from the toilet, of course, since most of our day would be simultaneously spent urinating. Instead, the kidneys choose to reabsorb the good stuff (water, certain electrolytes, etc.) to save us from this undignified fate.

So we can't trust the total amount of urine formed, because reabsoption of water and other stuff after it has been filtered leaves us with much less urine than was initially filtered.

Hold on, though, what about some substance that isn't reabsorbed by the kidney? For instance, there is something called inulin (not insulin) that is freely filtered by the kidney but not reabsorbed at all. So we could measure how much inulin is found in the urine per minute, and that would reflect how much fluid was initially filtered, even if most of the latter has been reabsorbed subsequently.

So have we done it yet? No, but we are getting close. The first complication is that the amount of inulin filtered will depend on the blood concentration of inulin. For example, even if the glomerular filtration rate was the same in each case, more inulin would be filtered per minute if there was buckets of it in the blood than if there was one lonely molecule of it in the whole body. It's logical, but it does mean that our calculations have to factor this in.

Let's derive an intuitive equation for this, by the following experiment. Say I detect 10 units of inulin in the urine produced over a 10 minute period. That would mean that the kidney was filtering 1 unit of inulin per minute, right?

inulin formation rate = (amount of inulin) ÷ (time taken)

OK, so how much blood (plasma, technically) is it filtering per minute? As we said, for that we need to know the blood concentration, which happens to be 100 units of inulin per litre.

Are you keeping up? If we know that we are filtering 1U of inulin per minute and that there are 100U of inulin per litre in the blood, how much blood (plasma) are we filtering per minute? That's easy:

(amount of inulin ÷ time taken) ÷ (blood concentration)

= 1U/min ÷ 100U/L

= 0.01 litres

Yay - done now? Well, we have got the right answer, so we could start there. But it wouldn't hurt to factor in some actual world considerations - it'll make our lives easier, I promise.

For instance, instead of taking the patient's entire urine sample and measuring every single molecule of inulin in it, we could just take a small sample of it and measure the concentration of inulin. It's really much, much easier. We do need a slight alteration of our equation though:

'concentration' = number of molecules ÷ volume of liquid

we'll have to multiply the concentration by the volume in order to get back the number of molecules of inulin required in our formula. In other words, we can use 'concentration' instead of 'amount' of inulin, provided we modify our formula thus:

[(urinary inulin concentration) × (volume of urine) ÷ (time taken)] ÷ [blood concentration]

But by luck, the (volume of urine) ÷ (time taken) is equal to the urinary flow rate.

So, in all it's grandeur, our equation is thus:

One last comment. You may have noticed we haven't mentioned 'creatinine clearance' much. The reason we used inulin is because it was freely filtered by the kidneys and not reabsorbed. The only disadvantage to inulin is that it has to be specially administered and monitored. Most clinicians use creatinine instead of inulin, since creatinine is present in the blood (plasma) and urine anyway. Like inulin, it is freely filtered, but it is also active secreted by the cells lining the renal tubule too. This extra urinary creatinine means we overestimate the glomerular filtration rate (GFR) by about 10-20% when using creatinine, but it is still a much more practical option.

(Edit: in my opinion, this post is perhaps too long and not focused enough. I've tried to remedy this with a follow-on overview post, here.)

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